Samara State Technical University, Department of Organic Chemistry, report. Recovery (2013) - Department of Organic Chemistry SamSTU Department of Organic Chemistry SamSTU

MINISTRY OF EDUCATION AND SCIENCE OF THE RUSSIAN FEDERATION FEDERAL STATE BUDGETARY EDUCATIONAL INSTITUTION OF HIGHER PROFESSIONAL EDUCATION “SAMARA STATE TECHNICAL UNIVERSITY” Department of Organic Chemistry M.V. LEONOVA, Y.N. KLIMOCHKIN METHODS OF RESTORATION IN ORGANIC SYNTHESIS Educational and methodological manual Samara Samara State Technical University 2012 1 Published by decision of the editorial and publishing council of SamSTU UDC 542.9+547.2, 547.3, 547.6 Leonova M.V., Klimochkin Yu.N. Reduction methods in organic synthesis: educational manual./ M.V. Leonova, Yu.N. Klimochkin - Samara, Samar. state tech. univ. 2012. 111 p.: ill.1 Reduction reactions of various classes of organic compounds are considered. The characteristics of some reducing agents and hydrogenation catalysts are given, and instructions are given for the selection of reduction methods. Methods for the synthesis of organic compounds of different classes based on reduction reactions are presented. For higher education students educational institutions students studying in chemical technology areas and specialties. M.V. Leonova, Yu.N. Klimochkin, 2012 Samara State Technical University, 2012 2 CONTENTS Introduction …………………………………………………… 1. Characteristics of reducing agents …………………... 5 7 2 Reduction of hydrocarbons……………………….. 3. Reduction of halogenated hydrocarbons.. 4. Reduction of alcohols, phenols and ethers.. 5. Reduction of aldehydes and ketones………………. 18 29 33 37 6. Reduction of carboxylic acids and their derivatives 7. Reduction of nitrogen-containing compounds……….. 8. Reduction of sulfur-containing compounds………. 50 59 72 9. Preparation of reducing agents and reduction catalysts ………………………………………………………... 10. Experimental part ……………………………. 11. Safety measures …………………………………… 12. Questions for self-control ……………………………... 82 101 105 Bibliography ……………………… …... Appendices ……………………………………………………… 108 109 3 74 LIST OF ABBREVIATIONS Ac – acetyl Alk - alkyl Ar – aryl AcOH – acetic acid Bu – butyl BuOH - butanol t-Bu – tert.butyl t-BuOH – tert.butanol 9-BBN - 9-borabicyclononane BINAP - 2,21-bis(diphenylphosphino)-1,11-binaphthyl Et – ethyl EtOH - ethanol Hal – halogen Het – hetaryl Kt – LTBA catalyst - lithium tris(tert-butoxy)aluminum hydride LTMA - lithium tris(methoxy)aluminum hydride Me – methyl Ph – phenyl Pr – propyl i-Pr – isopropyl i-PrOH – isopropanol THF – tetrahydrofuran Ts – tosyl (4-СH3С6H4SO2) Glyme – 1 ,2-dimethoxyethane DEG - diethylene glycol DIBAL-N - diisobutylaluminum hydride Diglyme - diethylene glycol dimethyl ether DMF - N,N-dimethylformamide 4 INTRODUCTION Reduction is a common method for the preparation of many organic compounds, both in the laboratory and in industry. Reduction and oxidation reactions are characterized by the process of electron transfer, with oxidation being the loss of electrons by a compound, and reduction being the gain of electrons. Therefore, during the reduction process, the reducing agent donates one or more electrons. Reduction in organic synthesis involves mainly two types of reactions: a) reactions, as a result of which the oxidation state of carbon atoms in organic compounds in molecules decreases. These reactions can take place either with the displacement of oxygen (with the release of water) or without the displacement of oxygen; b) reactions accompanied by a decrease in the oxidation state of N, S, P and other atoms in organic compounds. Reduction reactions are chemical transformations that result in a decrease in the oxidation state of the atom or atoms representing the reaction center of the original compound. When calculating the oxidation state, each shared pair of electrons is assigned entirely to the more electronegative of the partner atoms, and a pair of bonding electrons between atoms of the same element is divided between them. The charge remaining on the atom is conventionally considered to be its oxidation state. The formation of a bond between a carbon atom and any more electronegative atom is associated with an increase in its oxidation state by one, and, conversely, the formation of a bond with a less electronegative atom is associated with a decrease in the oxidation state by one. The following are the oxidation states of carbon atoms in some molecules: 5 OH H -4 C C H H H H O O -2 H C0 H H H H C +2 O H Agents that are good electron donors (alkali, alkaline earth metals, zinc, tin, iron, metal amalgams) are used as reducing agents , metal salts in the lowest oxidation state, complex metal hydrides, hydrazine, organomagnesium compounds, alkali metal sulfides and sulfites, sodium dithionite, etc.). The reducing agent is also hydrogen at the time of separation or in the presence of a catalyst. With a wide variety of reduction methods, the choice of a specific method depends on the nature of the initial substrate, the conditions for isolating the final product, its stability, and the possibility of restoring other functional groups. The same substance can be reduced by several methods. Depending on the nature of the substance being reduced and the expected result, appropriate reducing agents and reaction conditions are used. At the same time, by selecting conditions and reagents, it is possible to carry out reduction at different rates and obtain different products. The proposed manual does not claim to be a complete presentation of material on restoration methods. Here are the methods most widely used in laboratory practice. In this manual, for convenience and better understanding by students of methods for the reduction of organic compounds, theoretical material is presented in the following sequence. First, the characteristics and applications of reducing agents are given. Then, methods for the reduction of the main classes of organic compounds are considered: hydrocarbons, halogen derivatives, alcohols and phenols, aldehydes and ketones, carboxylic acids and their derivatives, nitrogen-containing and sulfur-containing compounds. Practical part 6 provides methods for producing hydrogenation catalysts used in laboratory practice, some reducing agents, and methods for the reduction of various classes of organic compounds. 1. CHARACTERISTICS OF REDUCING AGENTS 1. Alkali and alkaline earth metals have a low ionization potential and easily give up electrons. They are used in systems metal - liquid ammonia or amine, metal - alcohol, but sometimes also in aprotic solvents. Amalgams of alkali and alkaline earth metals are often used. They reduce carbonyl, nitrogen-containing compounds, and compounds with conjugated bonds. 2. Tin, zinc, iron and some other metals, as well as their salts in the lowest oxidation state in acidic, alkaline or neutral aqueous media, are the most accessible reagents that are often used in the recovery in industry and in laboratory conditions of a wide variety of oxygen-, sulfur - and nitrogen-containing compounds. 3. Boron and aluminum hydrides. For recovery in laboratory practice the following are used: diborane B2H6; borane complexes with amines R3N. BH3 (liquids or crystalline substances); complex of borane with dimethyl sulfide BH3. SМе2; borane complex with tetrahydrofuran; dibromoborane, used as a complex with dimethyl sulfide - HBBr2. SМе2; selective hydroborating reagent - 9-boracyclononane (9-BBN). 7 H B 9-BBN Diborane is usually prepared by reacting sodium borohydride with boron trifluoride etherate. THF 3 NaBH 4 + 4 BF 3 o 2 B 2H6 + 3 NaBF 4 0 - 10 C Currently, there is a ready-made reagent - a diluted solution of diborane in tetrahydrofuran, which must be stored at 0 ° C. This reagent is very active, but extremely flammable. Borane complexes with R3N amines. BH3 is non-flammable, but reacts with alkenes only at elevated temperatures (100°C). Among aluminum hydrides, the most common reagent for reducing multiple bonds is DIBAL-N diisobutylaluminum hydride (i-C4H9)2AlH. In industry it is obtained from 2-methylpropene, aluminum powder and hydrogen. o H3C CH2 4 + 2 Al + 50 - 70 C 3 H2 H3C 50 - 60 àòì 2 ((ÑH3)2CHCH2)2AlH DIBAL-N As a reagent, DIBAL-N can be used individually, or in the form of a 1M solution in toluene. In its individual state, the substance is pyrophoric, so it should be worked in an atmosphere of argon or nitrogen. Ether, benzene, toluene, and cyclohexane are used as solvents for reactions with DIBAL-N. Tetrahydrofuran forms a complex with this reagent. DIBAL-N easily attaches to the carbon-carbon triple bond even at low temperatures. Double bonds C=C8 undergo hydroalumination much more slowly, which makes it possible to convert alkynes, especially terminal ones, into alkenes. In addition, DIBAL-N easily restores many functional groups (COOR, CN, etc.). 4. Complex metal hydrides - LiAlH4, NaBH4 and others are capable of reducing organic compounds of many classes. Complex metal hydrides are nucleophilic in nature, supplying hydrogen along with a pair of electrons, i.e., a hydride ion. In a reduced compound they attack the electrophilic center. The most commonly used lithium aluminum hydride is LiAlH4. This reagent was discovered in 1947 and is prepared in ether according to the following scheme: 4LiH + AlCl3 → LiAlH4 + 3LiCl Lithium aluminum hydride is usually used as a solution or suspension in absolute ether or tetrahydrofuran, since it reacts with protic solvents. LiAlH4 is very soluble in ether (35 g of reagent per 100 g of ether). To achieve such solubility, prolonged boiling with excess ether is required. Complex alkoxyaluminum hydrides are obtained by the reaction of lithium aluminum hydride with the calculated amount of alcohol: LiAlH4 + 3 CH3OH → LiAl(OCH3)3H + 3 H2 LTMA When lithium aluminum hydride is exposed to an excess of tert-butyl alcohol, only lithium tris(tert-butoxy)aluminum hydride (LTBA) is obtained . LiAlH4 + t-BuOH → LiAl(O-t-Bu)3H + 3 H2 excess LTBA 9 Alkoxyaluminum hydrides are very selective reducing agents. For example, LTBA reduces the carbonyl group of α,β-unsaturated aldehydes without affecting the C=C bond. In addition, LTBA, taken in an equivalent amount, is able to reduce the aldehyde group without affecting the ketone group. Sodium borohydride was obtained in 1943. o 4 NaH + B(OCH3)3 250 C NaBH 4 + 3 NaOCH3 This complex hydride has proven to be very convenient for the reduction of various functional groups. It effectively reduces aldehydes, ketones, and acid chlorides. The reduction of NaBH4 can be carried out both in alcohols and in a water-alcohol mixture. However, the reactivity of this reducing agent is lower than that of lithium aluminum hydride and the reduction is often carried out in an alkaline medium, which increases the stability of NaBH4 in alcohols and aqueous-alcoholic solutions. Depending on the structure of the starting compound, complex metal hydrides are taken in an amount equal to the hydride equivalent. Hydride equivalent is the amount of reducing agent (including active hydrogen), expressed in moles, required to reduce 1 mole of the original compound. For example, LiAlH4 uses four hydrogen atoms for reduction, and its one hydride equivalent is 0.25 mol. The products of reduction of compounds of various classes with lithium aluminum hydride and its hydride equivalent are presented in Table 1. 5. Alcohols in the presence of aluminum alcoholates (RO)3A1 are used to reduce aldehydes and ketones (Meerwein-Ponndorf-Verley reaction). 10 6. Hydrazine H2N–NH2 is a reducing agent of –NO, -NO2, C=O groups, also acting on the carbon-carbon double bond. The reducing agent is not hydrazine itself, but the product of its transformation - diimide (HN=NH). It is produced by the oxidation of hydrazine, most often with hydrogen peroxide in the presence of copper sulfate as a catalyst. Table 1 Compounds, restored LialH4 Initial connection product RETHOD Rcho Rcho R2c = o Cloralgidride RCOCL complex Ethere Rch2chH2CHOH RCHOH amide RCONHR (secondary) amid ROMID RCONH2 (Primary) Oxy that rcooh oxim rch = noh nitro compound rno2 (aliphatic) Halides RHal Consumption LiAlH4 (hydride equivalent) 1 1 Alcohol RCH2OH 2 Alcohol R1CH2OH+R2OH 2 Tertiary amine RCH2-NR2 or aldehyde RCHO Secondary amine RCH2NHR Primary amine RCH2NH2 Primary amine RCH2NH2 or aldehyde RCHO Alcohol RCH2OH 2 Amine R CH2-NH2 3 Amine RNH2, etc. 6 Hydrocarbon RH 1 11 1 3 4 2 1 3 7. Hydride ion donors - used for the reduction of tertiary alcohols and other compounds that can easily form carbenium ions. Most often in the practice of organic synthesis, triethylsilane and organosilicon oligomer GKZh-94 are used: CH3 Si O H n 8. Sulfur-containing reducing agents. In industry, sodium sulfide Na2S, sodium hydrosulfide NaHS, sodium polysulfide Na2Sn (n=2.3...) are used. In di- and trinitro compounds, these reagents selectively reduce one nitro group without affecting the others. Sodium sulfite Na2SO3 is used for the reduction of diazonium salts to the corresponding arylhydrazines. Sodium dithionite Na2S2O4 reduces azo compounds to amines. Also used for the reduction of nitroso and nitro compounds, quinones and disulfides. 9. Hydrogen iodide HJ. This reagent is often used in laboratory practice for the reduction of aliphatic alcohols and ethers. 10. Molecular hydrogen - in the presence of catalysts, is used to reduce various organic compounds. The addition of hydrogen to organic compounds is called hydrogenation. Hydrogenation can be carried out under conditions of heterogeneous and homogeneous catalysis. Heterogeneous hydrogenation usually occurs on the solid surface of a metal catalyst and is caused by the activation of reagent molecules upon interaction with the surface. Reduction with hydrogen may be accompanied by hydrogenolysis. Hydrogenolysis (destructive hydrogenation) is the breaking of a carbon-carbon bond, carbon-heteroatom (N, S, O, etc.) or heteroatom-heteroatom in organic compounds under the influence of hydrogen. It is usually carried out in the presence of hydrogenation catalysts. The hydrogenation products are given in Table 2. compounds of various classes Table 2 Compounds (functional group) reduced by catalytic hydrogenation Reduced compound (functional group) Reduction product RCOCl RCHO, RCH2OH RNO2 RNH2 RCCR RCH=CHR, RCH2CH2R RCHO RCH2OH RCH=CHR RCH2CH2R RCOR RCH(OH)R, RCH2R RCN RCH2NH2 RCOOR1 RCH2OH (R1OH) RCONHR1 RCH2NHR1 C6H6 C6H12 ROH RH RCOOH RCH2OH 13 Catalysts for heterogeneous hydrogenation are chemical elements with incomplete d-shells, most often metals of group VIII of the periodic system: a) Raney nickel (Ra – Ni) – an active and universal catalyst . So-called skeletal catalysts or Raney catalysts are often used. There are seven known varieties of such catalysts, which are designated W1, W2, …….W7. They are prepared from a 1:1 alloy of nickel and aluminum (Raney alloy), containing a small amount of titanium (to increase brittleness). The alloy is crushed and then treated with alkali. In this case, the aluminum is washed out, and the hydrogen released is adsorbed by nickel: NiAl2 + 6NaOH + 6H2O → Ni + 2Na3 + 3H2 spongy Well prepared Raney nickel is pyrophoric and must be stored under a layer of solvent. After use, it is filtered from the reaction mixture (the metal should not remain dry) and dissolved in dilute nitric acid (a violent reaction!). The activity of Raney nickel largely depends on the hydrogenation conditions and can be varied within fairly wide limits by introducing appropriate substances into the reaction mixture. An increase in activity is achieved primarily by using palladium chloride and platinum as activators. A partial reduction in the activity of Raney nickel in order to use it for selective hydrogenation can be achieved by introducing zinc acetate and piperidine, pyridine or quinoline, a mixture of nicotinic acid, morpholine and pyridine, etc. b) Pt, Pt/C, PtO2.H2O (Adams catalyst) – platinum catalysts that allow the hydrogenation of most functional groups. 14 Platinum black is obtained in laboratory practice by reducing chloroplatinic acid with formaldehyde. H 2 PtCl 6 + H2O CH 2 O KOH Pt black powder The resulting black is washed with distilled water. When obtaining this catalyst, it is necessary to strictly observe the conditions for obtaining black, otherwise an inactive form of the catalyst may result. For hydrogenation, it is more convenient to use Adams catalyst PtO2. H2O. It is obtained by fusing chloroplatinic acid with sodium nitrate at 500-550°C. H2PtCl6 + NaNO3 → PtO2 yellow-brown After the release of NO2 ceases, the alloy is cooled and washed with water. The resulting oxide is PtO2. H2O is well preserved, and its reduction with hydrogen to platinum occurs directly in the reaction vessel. Supported platinum on Pt/C carbon can be prepared by the reaction of Na2PtCl6 salt with sodium borohydride in the presence of a carrier, for example: Na 2 PtCl 6 NaBH 4, C-form Pt/C o C2 H5OH, 25 C c) Pd, Pd/C, Pd/ CaCO3 and others – palladium catalysts. Free metal catalysts are not very easy to handle and require special precautions during storage. In addition, only a thin surface layer of metal takes part in catalytic processes, so it is advisable to apply a thin layer of catalyst to a substrate - “carrier”. 15 Various carriers are used: activated carbon, aluminum oxide, silicon oxide, sulfates and carbonates of barium, calcium and other metals, asbestos, pumice, kieselguhr, etc. For example, a calculated amount of sodium sulfate solution is added to a solution of barium chloride and then a solution of Na2PdCl4, which adsorbs on the surface of barium sulfate. This is followed by conventional reduction to the metal, for example with formaldehyde. Na2PdCl4 + CH2O + 3NaOH → Pd + HCOONa + 4NaCl + 2H2O A very active catalyst is palladium on Pd/C carbon. The role of the inert carrier is to increase the contact surface of the metal or other active component of the catalyst with the reacting substances. Therefore, the specific surface area of ​​the support itself and its structure affect the activity of the catalyst. In addition, its activity, selectivity and stability can often be increased by adding small amounts of other metals, salts, oxides or mineral acids called promoters (activators). Sometimes supported catalysts are complex compositions: Pd/CaCO3 + Pb(OCOCH3)2 – the Lindlar catalyst is effective for the selective hydrogenation of triple bonds to cis double bonds; Pd/BaSO4 + S8/quinoline - Rosenmund catalyst. d) oxide (MgO, ZnO, Cr2O3, Fe2O3, etc.) are used in industry. ), complex oxide (ZnO + Cr2O3, CuO + Cr2O3, CuO + CuCr2O4), sulfide (FeS, CoS, Re2S7, MoS2, NiS, WS2, etc.) and multicomponent catalysts, including compounds of titanium, vanadium, aluminum, magnesium, zinc . 16 The Adkins catalyst is copper chromite, a complex inorganic compound with the composition Cu2Cr2O5, which is used for catalysis in organic synthesis. Homogeneous hydrogenation. Some transition metal complexes are capable of catalyzing the hydrogenation of alkenes and alkynes. Since these complexes are soluble in organic solvents and are in the same phase with the starting reagents, such hydrogenation is called homogeneous. The catalysts for homogeneous hydrogenation are: (Ph3P)3RhCl – Wilkinson catalyst; IrCl(CO)(Ph3P)2 - catalyst Vaska et al. When hydrogenating alkenes or alkynes in the presence of transition metal complexes, the groups NO2, COOR, CN, C(O)R are not affected, for example: Ph CH CH NO 2 + H2 (PPh 3) 3RhCl CH 3COC 2H5 Ph CH2 CH2 NO 2 44% The advantages of homogeneous hydrogenation over heterogeneous hydrogenation are: - better reproducibility of results; - absence of hydrogenolysis of C-O and C-N bonds; - high selectivity; - insensitivity to catalytic poisons. The use of chiral ligands allows for asymmetric hydrogenation of C=C, C=O or C=N bonds. One of the chiral ligands most used for this purpose is 2,21bis(diphenylphosphino)-1,11-binaphthyl (BINAP). 17 PPh2 PPh2 (R)-(+)-BINAR 2. REDUCTION OF HYDROCARBONS Hydrocarbon reduction reactions can be divided into two types: 1. Addition of hydrogen through multiple bonds: CH CH H2 CH2 CH2 H2 CH3 CH3 2. Reactions with hydrogen accompanied by the splitting of carbon - carbon bonds (destructive hydrogenation or hydrogenolysis). Open-chain hydrocarbons, cycloalkanes, and aromatic compounds with a side chain are capable of these reactions. Alkanes and cycloalkanes. Hydrogenolysis of alkanes is usually carried out on industrial reforming catalysts, for example, Pt/Al2O3 at 285°C, which leads to their conversion into lower molecular weight hydrocarbons. During hydrogenolysis, any C-C bonds in alkane molecules can be broken. The methane content in the reaction products increases significantly with an increase in the degree of branching of the 18 hydrocarbon and, consequently, with an increase in the number of methyl groups. Hydrogenolysis of alkanes using ethane as an example can be represented by the following scheme: CH3 H2 CH3 Kt 2 CH4 Under the influence of hydrogen in the presence of a catalyst, ring opening occurs in cycloalkane molecules. Catalytic hydrogenolysis of cyclopropanes occurs very easily. Cyclobutane is less reactive and ring opening during hydrogenolysis occurs under more stringent conditions. H2/Ni 80°C H2/Ni 180°C H2/Ni 300°C Alkenes and dienes The addition of hydrogen through an isolated double carbon-carbon bond in the presence of noble metals and Raney nickel usually occurs easily at a temperature of 20 - 25 ° C and a hydrogen pressure of 1 - 4 atm. The reaction rate depends on the structure of the compound and in the series of alkenes and cycloalkenes decreases with increasing degree of substitution of the ethylene fragment (Lebedev's rule). Ethylene is hydrogenated most quickly, and for its homologues the reaction rate due to the screening effect of substituents falls in the following order: 19 R H2 C CH2 CH2 > > R R R > CH2 > R R > R R R R R > R The stereochemical result of hydrogenation largely depends on the nature of the catalyst and reaction conditions. C H H catalyst C CH catalyst C H CH CH catalyst In the above diagrams it can be seen that both hydrogen atoms approach the carbon atoms of the double bond from the surface of the metal catalyst. And usually the addition occurs on only one side of the double bond. In this case, the substrate molecule faces the surface of the catalyst, as a rule, with its spatially less obstructed side. If the alkene binds to the catalyst sufficiently strongly, then as a result of hydrogenation, the synaddition product* is predominantly formed. However, with less strong binding of the alkene to the catalyst surface, the addition of hydrogen occurs in steps. After the addition of the first hydrogen atom, both a change in the position of the substrate molecule on the catalyst surface and various isomerization processes can occur. In this case, the predominant direction of the reaction may be anti-addition. The stereochemical result of hydrogenation may vary depending on the catalyst used. Thus, platinum catalysts produce mainly a syn-addition product, and when using a palladium catalyst, an anti-addition product is often formed. For example, during the hydrogenation of 1,2-dimethylcyclohexene on PtO2 in acetic acid at 25°C and atmospheric pressure a product is formed containing 82% cis isomer and 18% trans isomer. When the hydrogen pressure increases to 500 atm, the content of the cis isomer increases to 95%. ___________________________________________________________________ *Syn addition - when two fragments of a reagent are added to the same side of a multiple bond. In cases where atoms or groups of atoms are added with different sides multiple bond, anti-addition occurs. The terms syn- and anti- are equivalent in meaning to the terms cisi trans-. It should be taken into account that the terms syn- and anti- refer to the type of attachment, and the terms cis- and trans- to the structure of the substrate. H C H 3 H2, Pd/C H2, PtO 2 H o AcOH, 25 C H3C H 73% trans-1,2-dimethylcyclohexane H o AcOH, 25 C H3C CH3 1,2-dimethylcyclohexene H3C CH3 82% cis-1,2 -dimethylcyclohexane Hydrogenation of 1,2-dimethylcyclohexene on Pd/C leads to the formation of a mixture of 1,2-dimethylcyclohexane isomers, in which the trans isomer predominates (73%). The hydrogenation reaction is exothermic. An important feature of most hydrogenation reactions is their reversibility (dehydrogenation). The reduction of alkenes to the corresponding alkanes can be accomplished using diimide NH=NH. Diimide can be obtained by two main methods: the oxidation of hydrazine with hydrogen peroxide 21 in the presence of Cu2+ ions or the reaction of hydrazine with Raney Ni. CH3 CH3 NH2NH2 H CH3 Ni - Raney CH3 H cis-1,2-dimethylcyclopentane 1,2-dimethylcyclopentene A distinctive feature of this method is that the reduction process occurs as a syn addition. An indirect method for the hydrogenation of unsaturated compounds involves the interaction of alkenes with boron hydrides. This method is called hydroboration. The reaction of diborane B2H6 with an alkene occurs as a syn addition to a double bond, for example: CH3 CH3 CH3 H + B2H6 BH2 CH3 CH3 CH3 H H) B 3 B H H CH3 Subsequent decomposition of the resulting tris(2-methylcyclohexyl)borane with acetic acid leads to the hydrocarbon: CH3 H CH3 AcOH 3 + B(OAc) 3)3 B If the alkene is unsymmetrical, then the boron atom attaches preferentially to the least substituted carbon atom (the most hydrogenated), i.e. against Markovnikov's rule. 22 H3C CH CH2 B2H 6 H3C CH2 CH2 BH2 ..... (H3C CH2 CH) B 23 This direction of addition is caused primarily by spatial effects. Under the influence of acids in alkylboranes, the C-B bond is cleaved, with a proton attacking a carbon atom carrying a partially negative charge: (R CH2 +  CH2)3 B   3 R CH2 CH3 For the cleavage of the C-B bond, it is most effective acetic acid, since the boron atom tends to form bonds with oxygen. Straight chain dienes hydrogenate faster than olefins. Depending on the structure of the diene, hydrogen can be added first to the 1,4-position or simultaneously to the 1,2- and 1,4-positions. Complete hydrogenation leads to alkanes. 1.2H2C CH CH CH2 H2 H3C CH2 CH CH2 H2 1,4- H3C CH CH H3C CH2 CH2 CH3 CH3 Conjugated dienes undergo addition reactions more easily than non-conjugated dienes. Hydrogenation of conjugated dienes under heterogeneous catalysis usually leads to alkanes. It is possible to selectively reduce a diene to produce an alkene under the action of sodium amalgam in an aqueous-alcoholic medium or with sodium in liquid ammonia. In this case, 1,4-addition products (E- and Z-isomers) are formed: 23 Na NH3 liquid. CH2 CH CH CH2 CH3 CH Na (Hg) CH CH3 H2O, EtOH 1,3-butadiene 2-butene Alkynes Reduction of acetylene hydrocarbons can proceed completely into saturated compounds or partially into ethylene compounds. Complete hydrogenation is usually carried out under mild conditions (25°C, 1 – 5 atm) on palladium, platinum and active nickel catalysts: CH3 C CH H2 Kt CH3 CH CH2 H2 CH3 CH2 CH3 Kt Much more practical significance has partial hydrogenation of acetylenes. In this case, the most suitable catalysts are palladium catalysts, partially deactivated with lead acetate (Lindlar catalyst), and nickel catalysts (skeletal, etc.). For example: R 1 R 2 H2, kàò. Linear R 1 R 2 o EtOH, 0-20 C H H cis-alkene The rate of hydrogenation of the triple bond on these catalysts is higher than the double bond, while on other catalysts there is no such difference, or the double bond is hydrogenated at a higher rate (especially if these are terminal communications). Alkynes can also be reduced by solutions of metals in liquid ammonia. This process is stereoselective and the products 24 of the reduction of disubstituted alkynes are alkenes having the E configuration (trans-), for example: CH3 CH2 C C CH2 COOH H CH3 CH2 Li C C THF, NH3 CH2 COOH H This method successfully complements catalytic hydrogenation, which produces alkenes with Z -configuration (cis-). Aluminum hydrides are used to reduce alkynes in organic synthesis. The addition of aluminum hydrides at multiple bonds is called the hydroalumination reaction. The most popular reagent for these reactions is diisobutylaluminum hydride - (i-C4H9)2AlH (DIBAL-N). A distinctive property of this reagent is the ease of addition at the carbon-carbon triple bond, even at low temperatures. Double bonds undergo hydroalumination much more slowly. This allows alkynes, especially terminal alkynes, to be converted into alkenes. R C CH + (i-Bu)2AlH -20oC toluene R H H CH 3OH Al(i-Bu)2 R H H H When reduced by aluminum hydrides, the aluminum atom preferentially bonds with the less substituted carbon atom. Arenas The stability of the aromatic system determines its lower reactivity during hydrogenation compared to olefins. Thus, the relative rates of hydrogenation of benzene, cyclohexene and the double bond in styrene are: 25 900 150 1 Benzene is much more difficult to hydrogenate than unsaturated hydrocarbons. It is assumed that the addition of hydrogen atoms coming from the surface of the catalyst to the adsorbed molecule occurs in stages. The first stage comes with the absorption of energy. Subsequent stages are exothermic and their speed is much higher than that of the first stage. As a result, it is impossible to isolate intermediate products (cyclohexadiene and cyclohexene) during the hydrogenation of benzene. 3 H2 N i For the hydrogenation of benzene, its homologues and derivatives, platinum and rhodium catalysts are used, in some cases highly active grades of skeletal nickel at temperatures of 25 - 50 ° C and a hydrogen pressure of 1 - 3 atm. Benzene homologues are hydrogenated at a lower rate than benzene itself. In alkenylbenzenes, the side chain is reduced first. Depending on the reaction conditions and catalyst, complete hydrogenation of the aromatic ring and side chain or selective hydrogenation of the side chain can be carried out: C2H5 4 H2 CH CH2 Ni 26 H2 Cu C2H5 Aromatic hydrocarbons with condensed nuclei are hydrogenated stepwise, with the bonds of one ring being saturated first. Hydrogenation of naphthalene proceeds through the following stages (with intermediate isomerization of 1,4-dihydronaphthalene into the more stable 1,2-isomer): 8 1 7 H2 2 6 H2 3 4 5 1,4-dihydronaphthalene and 1,2-a range 3 H2 When anthracene is hydrogenated to positions 9 and 10: 8 9 1 7 2 6, the first addition occurs Reduction of aromatic rings by the metal-ammonia system is the most used method of reduction in organic matter. synthesis. Solutions of metals in liquid ammonia act as agents powerful enough to reduce the aromatic ring, and at the same time specific enough to ensure that the reduction occurs only partially to dihydrobenzenes (cyclohexadienes). This type of reaction is known as Birch reduction. The ease of reduction decreases in the order: anthracene > phenanthrene > naphthalene > diphenyl > benzene Benzene itself cannot be reduced by an alkali metal in liquid ammonia, and its reduction can be successfully carried out to 1,4-dihydrobenzene only in the presence of a proton donor that is more effective than ammonia , such as ethanol: Na, EtOH NH3 (æ) This type of reduction is also observed for substituted benzene derivatives. Chemoselectivity is a unique feature of Burch reduction, since the main products are non-conjugated dienes. When replacing sodium with lithium, the yields of diene products increase. When lithium is used, recovery is achieved even in cases where sodium is not effective. In this method, alcohol is added at the end of the reaction. To increase the solubility of the starting material, ether or tetrahydrofuran is often added to the reaction mixture. The reaction mechanism in the first stage involves the transfer of an electron from the metal to the aromatic compound to form a radical anion (1). Protonation of this radical anion with an alcohol results in radical (2), which then gains another electron, giving anion (3). Protonation of the latter with alcohol leads to cyclohexadiene (4). 28 H H . . + M=Li, Na . ROH - RO M NH3 - H H . + H - . M H H H H (2) ROH NH3 - RO H H H (1) H - H (3) H (4) The Birch reaction slows down in the presence of electron-donating substituents in the aromatic compound molecule, since they complicate the first slow stage of the reaction - the transfer of an electron from the alkali metal to the molecule aromatic compound. In this case, substrates containing an electron-donating substituent form 1-substituted 1,4cyclohexadiene. O O Na CH3 CH3 NH3(æ) 80% Reduction of substrates with electron-withdrawing substituents leads to the formation of 3-substituted 1,4cyclohexadiene. - COOH ÑOO Na Na , NH3(æ) + COOH H3 O EtOH 29 + It should be noted that most acceptor groups under the conditions of the Birch reaction are reduced themselves, and in the first place. Therefore, a significant proportion of examples of the Birch reduction of aromatic derivatives containing electron-withdrawing groups are associated with the reduction of aromatic acids or their amides. In cases where ammonium acetate is used as a source of protons, the amide group is reduced to an aldehyde. 3. RESTORATION OF HALOGENA DERIVATIVES OF HYDROCARBONS Hydrogenolysis of halogen derivatives occurs easily on various catalysts. The nature of the carbon-halogen bond (type of halogen) and the reaction conditions, primarily temperature, are of decisive importance in the hydrogenolysis of halogen derivatives. In general, the resistance to hydrogenolysis of the carbon-halogen bond changes in the following order: iodine-< бром- < хлор- < фторпроизводные Йод- и бромалканы легко восстанавливаются на скелетном никелевом катализаторе в присутствии гидроксида калия при температуре 25оС и атмосферном давлении. Хлориды в этих условиях подвергаются гидрогенолизу медленнее. Алкилфториды восстановить с приемлемыми выходами даже в жёстких условиях практически не удаётся. В случае непредельных галогенпроизводных восстановительное дегалогенирование протекает особенно легко, если атом галогена находится в аллильном или пропаргильном положении. При этом во всех случаях восстанавливается и кратная связь. 30 R CH CH CH2Br H2 R CH2 CH2 CH3 Ni В ароматических соединениях атом галогена в бензильном положении замещается водородом намного легче, чем атом галогена, находящийся в ароматическом кольце. Дегалогенирование может быть осуществлено без восстановления бензольного кольца. Прекрасным катализатором гидрогенолиза галогенпроизводных разных типов является никель Ренея. Дегалогенирование арилгалогенидов проводят в присутствии щёлочи и обычно при температуре 25оС и давлении 1 – 3 атм: Br OH OH H2 o Ni, 25 C O CH3 O CH3 Арилгалогениды на оксиде платины при температуре 50-70оС и давлении 3 атм не только подвергаются гидрогенолизу, но и полностью гидрируются, давая циклоаланы с выходом 70-95%, например: R H2 PtO2, EtOH, 55oC, 3атм R=Br, Cl При действии комплексных гидридов металлов на первичные и вторичные алкилгалогениды происходит замещение галогена водородом: H3C CH2 LiAlH 4 CH2 Br ýôèð 31 H3C CH2 CH3 Бензил- и аллилгалогениды при действии алюмогидрида лития претерпевают восстановительное расщепление легче, чем арилгалогениды. Это иногда позволяет провести процесс селективно. Cl Cl LiAlH 4 ýôèð CH3 Br Присутствие электронодонорных заместителей в орто- или параположении арилгалогенидов оказывает positive influence on the speed of reaction. Non-activated aryl fluorides and aryl chlorides are not reduced by complex metal hydrides, but aryl bromides and aryl iodides are easily reduced. This makes it possible to selectively reduce polyhalogen derivatives, for example: Cl LiAlH 4 Cl ýôèð I A common dehalogenation method is to treat the substrate with lithium metal and tert-butyl alcohol in tetrahydrofuran. This reducing system replaces halogen in alkyl, vinyl, allylic, aromatic halides. This method can even remove the halogen located at the head of the bridge of the bicyclic system and restore geminal dihalogen derivatives, for example: 32 Cl Cl Li + t - BuOH THF Another way to replace a halogen with hydrogen is to react the halogen derivative with magnesium in ether and subsequent hydrolysis of the resulting Grignard reagent: R Hal + Mg H2O R MgHal ýôèð R H Grignard reagent Alkyl halides, allyl and benzyl halides react especially easily in this way. Halogen derivatives of the aliphatic series are reduced with hydrogen iodide just as well as alcohols: R R I + HI H + I2 Iodides react most easily, and some chlorinated derivatives practically do not react with hydrogen iodide. 4. RESTORATION OF ALCOHOLS, PHENOLS AND ETHERS Alcohols and phenols are very resistant to the action of reducing agents. They are often the end products of the reduction of various carbonyl compounds. For the catalytic reduction of alcohols, the most effective catalysts are Raney nickel, copper and iron catalysts at a temperature of 250 - 300 ° C: 33 H2 OH H3C Ni H3C CH3 In laboratory practice, it is more convenient to reduce aliphatic alcohols to alkanes by the action of hydrogen iodide. This is the classic method of replacing a hydroxyl group with hydrogen (deoxygenation). The reaction is carried out in two stages. At the first stage, the hydroxyl is replaced by a hydrogen atom: R OH + HI R I + H2O At the second stage, the alkyl iodide is reduced with a second molecule of hydrogen iodide to form an alkane and iodine: R H + R I + HI I2 The disadvantage of this method is the use of a large excess of a rather expensive reagent - hydrogen iodide. Benzyl alcohols are more easily reduced than aliphatic ones. According to their ability to be reduced, they can be arranged in the following series: HO C > HO CH > CH2OH The reduction of phenols occurs under more severe conditions. Phenols are not reduced by chemical reducing agents; they mainly resort to catalytic reduction, and the direction of the reaction is determined by the hydrogenation conditions and the catalyst. In industry, cyclohexanol is produced in significant quantities by hydrogenation of phenol, which is used in the production of polymer materials. The process of reducing phenol to cyclohexanol with hydrogen is carried out on a nickel catalyst at elevated hydrogen pressure (1.5-2.5 MPa) and a temperature of 140-150°C: OH OH 3H2, Ni/Cr 2O 3 o 140-150 C phenol cyclohexanol Incomplete reduction is also possible phenol to cyclohexanone. The reaction is carried out on a palladium catalyst: OH O OH 2H 2 Pd/Al 2O3 o 110-140 C 88-92% phenol cyclohexanone Tertiary fatty aromatic alcohols are almost quantitatively reduced to hydrocarbons by the action of zinc in acetic acid: Zn OH triphenylcarbinol + 2 CH 3COOH triphenylmethane 35 (CH 3COO) 2Zn + H2 O Primary and secondary fatty aromatic alcohols are reduced to the corresponding hydrocarbons by the action of sodium in alcohol: Na OH CH2 EtOH diphenylcarbinol (benzhydrol) diphenylmethane Tertiary, as well as benzyl and allylic alcohols, are effectively reduced when treated with silanes in the presence of Lewis acids: R3 COH BF3 + R3 C R"3 SiH R3 CH Another example of the reduction of tertiary alcohols by hydride ion donors is the reaction of 1-alkyl-1-cyclohexanol with triethylsilane in trifluoroacetic acid to form a hydrocarbon: R (C 2H5)3SiH OH R CF 3COOH Reduction of ethers adiphatic series occurs with splitting S-O connections . For example, when exposed to hydrogen iodide in acetic acid upon heating, ethers are split to form a mixture of alcohols and alkyl halides. 36 O H3 C HI OH H3 C CH3 + Reduction of oxiranes with hydrogen to the corresponding alcohols, for example: H2 O H3 C I leads to H3 C o Ni, 100 C OH Reduction of oxiranes with lithium aluminum hydride leads to ring opening with the formation of a secondary or tertiary alcohol. The reaction consists of a nucleophilic attack of the hydride ion at the least substituted carbon atom: CH3 O CH3 o 1. LiAlH 4, THF, O C OH 2. H2 O 83% In unsaturated ethers, hydrogen is added via a multiple bond: O O H2 CH3 o Ni, 20 C vinyl phenyl ether phenetol Hydrogenation of diphenyl ether occurs under harsh conditions: O OH H2 o Fe, 485 C 37 + 5. REDUCTION OF ALDEHYDES AND KETONES The reduction of aldehydes and ketones is distinguished by a wide variety of methods, therefore, for convenience, the material in this section is presented depending on the type of reducing agent used . Catalytic hydrogenation Under catalytic hydrogenation conditions, aldehydes are reduced to primary alcohols, and ketones are reduced to secondary alcohols. All metal catalysts are suitable for the reduction of carbonyl compounds with hydrogen. The most effective are platinum and active grades of skeletal nickel. On these catalysts, as well as on rhodium and ruthenium, most aldehydes and ketones are hydrogenated at a temperature of 25 ° C and a pressure of 1 - 4 atm. With less active varieties of Raney nickel, a sufficient reduction rate is achieved at temperatures up to 100 - 125oC and pressures up to 100 atm: O H2 H O R OH PtO2 (Ni), 25oC, 3 atm HO H2 CH3 R Ni, 25-30o C, 1-3 atm CH3 R =Me, Ph During partial hydrogenation of ,-unsaturated aldehydes and ketones, only the C=C bond reacts: O H2 R H O o Pd/Al 2 O3, 25 C, 2 àòì 38 R H 88% The reactivity of aldehydes and ketones during reduction is due to electronic and spatial factors. Thus, aldehydes are reduced more easily than ketones, and formaldehyde is reduced more easily than acetaldehyde. With complete hydrogenation (2 mol of hydrogen) ,-unsaturated aldehydes and ketones on Raney nickel, a saturated alcohol is formed: O H2 H OH Ni, 125oC, 100 atm crotonaldehyde 94% butanol-1 If the carbonyl group is associated with an aromatic ring, then the resulting during hydrogenation, the alcohol can then undergo hydrogenolysis under the same conditions: O H2 Ar Kt R OH Ar H2 Kt Ar CH2 R + H2 O R Many aromatic carbonyl compounds on copper chromite or Raney nickel undergo hydrogenolysis, for example: O H2 CuCr2O4, EtOH, 175oC , 100-150 atm diphenyl ketone diphenylmethane Catalysts such as rhodium and ruthenium make it possible to minimize the hydrogenolysis of the C-O bond. 39 OH OH O CH3 H2 (3 atm), 5%Rh/Al2O3 C2H5OH, 50oC CH3 OH 78% During hydrogenation on platinum-rhodium catalysts in ethanol or acetic acid at a temperature of 20-90oC and a pressure of up to 5 atm, the benzene ring is also reduced : H3С O H3C H2 OH RhO2 - PtO2, EtOH (AcOH) 94% acetophenone 1-phenylethanol For the reduction of aromatic ketones, catalysts such as palladium on carbon and copper chromite are most often used, since the hydrogenation of the aromatic ring occurs very slowly on these catalysts. During partial hydrogenation of aromatic unsaturated ketones, reduction occurs only at the C=C bond: O CH CH C CH3 H2 O CH2 CH2 C CH3 Pt/C Thus, the multiple carbon - carbon bond interacts with hydrogen faster than the carbonyl group. Reductive amination 40 If the hydrogenation of aldehydes and ketones is carried out in the presence of ammonia, primary or secondary amines, then instead of alcohols the corresponding primary, secondary or tertiary amines are obtained (reductive amination). For these purposes, skeletal nickel (40-150°C, 3-150 atm) or platinum (25°C, 1-3 atm) catalysts are usually used. R1 O R2 NHR 3R4 R1 NR 3R4 R2 R1 H2 OH CH NR 3R4 + H2 O R2 Kt R4 =H (R 3 =R 4 =H) - H2 O R1 C R2 NR 3 H2 Kt R1 CH NR 3 R2 It is assumed that the intermediate products here are azomethines or enamines. When carrying out reductive amination, one must take into account the possibility of side reactions, including the formation of amines with a higher than specified degree of alkylation. The preferential production of an amine with the required degree of alkylation is determined by the ratio of the reagents. To obtain monoalkylation products, the amine component is usually taken in excess. Of the aliphatic aldehydes, only compounds containing more than five carbon atoms are well suited to catalytic reductive amination, while lower aldehydes easily form condensation products (such as aldols) during the reaction. The reaction proceeds smoothly in the case of aliphatic and aromatic ketones and aromatic aldehydes. Reductive amination of aldehydes or ketones can also be carried out by the action of ammonium formate or formamides (Leukart-Wallach reaction): 41 O R C O + R H C N R1 R2 R3 R2 CH N - CO2 R1 R3 The reaction is carried out at 50-200 ° C in formic or acetic acid, or without a solvent. Yields of final products are 70-75%. Tertiary amines are obtained best according to Leuckart-Wallach. When producing primary or secondary amines, highly alkylated amines are always formed as by-products. Modification of the Leuckart-Wallach reaction - obtaining Nmethylated amines by reacting primary or secondary amines with formaldehyde and formic acid (Eschweiler-Clark reaction). 100o C R2 N H + CH2 O + HCO OH R2 N CH3 Reduction with complex metal hydrides Complex metal hydrides are more often than other reagents used in laboratory practice for the reduction of aldehydes and ketones. Lithium aluminum hydride and sodium borohydride reduce aliphatic aldehydes and ketones, respectively, to primary and secondary alcohols: O H3 C LiAlH 4 ýôèð H3C CH2 OH H O H3 C CH3 LiAlH 4 ýôèð OH H3 C CH3 When reduced by lithium aluminum hydride, the complex ion AlH4- acts as a hydride carrier -ion, which is the 42 nucleophilic agent of the carbonyl group: in relation to the C O atom R R carbon R R AlH4- R to C O - H2O R C OH H H Reduction of ,-unsaturated aldehydes and ketones with lithium aluminum hydride or sodium borohydride depending on the structure of the substrate, nature reagent and reaction conditions can occur either at the carbonyl group or with the reduction of both the carbonyl group and the double bond. As a rule, these reagents reduce predominantly the carbonyl group without affecting the double bond: O LiAlH4 HO ... 2 ester H OH crotonic aldehyde crotyl alcohol In some cases, the use of these reducing agents leads to a mixture of two products. O OH NaBH 4 + EtOH 2-cyclohexenone OH 2-cyclohexenol 59% cyclohexanol 41% In the case where the double bond is conjugated to an aromatic ring, reduction with lithium aluminum hydride can occur at both the double bond and the carbonyl group: 43 O H LiAlH4 ether cinnamaldehyde OH hydrocinnamic alcohol Aluminum alkoxyhydrides are the preferred reagents for the reduction of unsaturated aldehydes and ketones to the corresponding unsaturated alcohols. For example, lithium tris(tert-butoxy)aluminum hydride (LTBA) reduces the carbonyl group of α,β-unsaturated aldehydes without affecting the double bond. O H LiAl (O-t-Bu)3 H cinnamaldehyde OH cinnamic alcohol LTBA, taken in an equivalent amount, is capable of reducing the aldehyde group without affecting the ketone group: O H LiAl (O-t-Bu)3 H OH O O Reduction by dissolving metals Before the introduction into laboratory practice of such reducing agents as complex metal hydrides, ketones were converted into the corresponding alcohols by the action of sodium in ethanol: 44 OH O Na EtOH + 65% The mechanism of reduction by dissolving metals is the transfer of an electron from the metal to an organic substrate and can be represented by the diagram: . R + O R Na CH R" O R - R" R" R. . O Na - Na+ - . O N a+ -NaOEt- R" R CH O H3O+ - R" EtO H R CH OH R" Such reactions involve two successive transfers electron and two proton transfers. Clemmensen reduction When amalgamated zinc acts on aldehydes and ketones in hydrochloric acid, they are reduced to hydrocarbons (Clemmensen method): O R R CH2 2 Zn/Hg, 4HCl + 2 ZnCl2 45 + H2O Zinc dust is pre-treated with dilute hydrochloric acid to clean the surface, and then with a solution of mercuric chloride HgCl2. The best results are obtained when the reaction is carried out in a two-phase system “hydrochloric acid - toluene”. Many α-substituted ketones undergo reductive elimination of the substituent under the conditions of the Clemmensen reaction: R CH C R" X O Zn/Hg HCl, R CH2 C O R" R CH2 CH2 R" X=Cl, Br, I, OH, OR", OCOR" In the case α, β - unsaturated carbonyl compounds, the C=C bond is simultaneously reduced, for example: Zn/Hg, COOH HCl, COOH O compounds The Clemmensen method gives good yields of hydrocarbons in the reduction of many aldehydes and aliphatic and fatty aromatic ketones. In the case when aldehydes and ketones are unstable in an acidic environment, the reduction is carried out using the Kizhner-Wolf method. First, the hydrazone of the aldehyde or ketone is prepared, and then heated with an alkali in a high-boiling solvent. 46 N2H 4 R R O 1 R ÄÝÃ, R 1 N NH2 R KOH, H 2O R 1 + CH2 N2 In the modern modification of the Kizhner-Wolf reduction, hydrazone is not isolated in the individual state.The reaction proceeds according to the following scheme: N2 H 4 R R R O 1 -H 2 O R 1 HO - R R N NH2 R N NH 1 - - C R N NH 1 H2 O R R 1 H H2 O R R H C H R 1 H -N 2 R N 1 - N HO - R H R N NH 1 The method is applicable to both aldehydes and ketones. However, in the case of aldehydes, the yields of reaction products are not always satisfactory. The Kizhner-Wolff method has a number of limitations. If there is a substituent in the α-position to the carbonyl group, then the substituent is eliminated during the reaction. If the carbonyl group is shielded by very bulky substituents, the Kizhner-Wolf reduction will not work. Reduction in the presence of metal alkoxides Reduction of aldehydes and ketones to alcohols can be carried out in the presence of aluminum alkoxides (Meerwein – Ponndorff – Verley reaction): 47 R OH C O ((CH3)2CHO)3Al + RR1CHOH + H3C CH3 H3C R1 O CH3 The reaction is usually carried out by heating carbonyl compound with aluminum isopropylate in anhydrous isopropanol. The reaction is reversible, therefore, to achieve high yields, it is necessary to remove the resulting acetone from the reaction sphere. The Meerwein–Ponndorff–Verley reaction is characterized by a high degree of specificity and during reduction, double and triple carbon-carbon bonds remain unaffected. The nitro group and halogen atoms are also not reduced under these conditions. For example, the reduction of crotonaldehyde proceeds with the preservation of the double C=C bond: O O i-PrOH H3C H ((CH3)2CHO)3Al crotonaldehyde H3C OH + H3C CH3 crotyl alcohol Double carbon - carbon bond in unsaturated aldehydes and ketones can be restored if necessary the action of sodium amalgam in an aqueous-alcohol solution or zinc in acetic acid. Cannizzaro reaction Aromatic and aliphatic aldehydes incapable of enolization under the influence of basic catalysts (hydroxides of alkali and alkaline earth metals) are disproportionated to form carboxylic acids and alcohols (Cannizzaro reaction). Reaction 48 involves two aldehyde molecules: one of them is oxidized, the other is reduced. O 2 R C - O HO H + R C H R CH2 OH OH For enolizable aldehydes, the rate of the aldol reaction is much greater than the rate of the Cannizzaro reaction, so only the first of these reactions practically occurs. It is believed that the reaction proceeds as follows: O C H + H C C H C + H O- O- OH OH H OH O O OС - HO C + O C H H A H + O C B 1) In the first stage, nucleophilic addition of hydroxide- ion to the carbonyl carbon atom. 2) This is followed by the transfer of the hydride ion from the formed alkoxide ion to the carbonyl atom of another aldehyde molecule. 3) At the third stage, a proton is transferred from the acid to the alkoxide ion. The resulting acid molecule and alcoholate ion A are transferred as a result of proton exchange into a more stable pair: an alcohol molecule and an acid anion B. If the Cannizzaro reaction is carried out with a mixture of aldehyde and formaldehyde, then the latter always acts as a donor of hydride49 ion and is oxidized to formic acid (Cannizzaro cross reaction): O HO H CH2 O + - HO H H O + H OH This is explained by the fact that formaldehyde attaches a hydroxide ion more easily than other aldehydes, which have reduced electrophilicity of the carbonyl carbon atom. Reductive coupling according to McMurry A specific method for the reduction of carbonyl compounds is the formation of alkenes by the action of titanium compounds on aldehydes and ketones in lower oxidation states. This method is called McMurry reductive combination. When aldehydes and ketones are exposed to a reagent that is obtained by reducing titanium salts (III or IV) with zinc metal in pyridine, they double, for example: O Zn + TiCl4 = 90% Reduction of quinones Quinones by their nature are conjugated cyclic diketones. They have a high oxidation potential and are very easily reduced by various reagents to up to 50 dihydroxyaromatic compounds. Benzoquinones, naphthoquinones, and anthraquinones are of greatest practical importance. The transition of benzoquinones into diatomic phenols leads to a gain in energy, since the transformation of the cyclic diene structure into an aromatic one takes place: O OH _ + 2H+ 2e _ (- 2e) O OH 1,4-benzoquinone hydroquinone To reduce quinones in laboratory practice, hydrogen iodide is used, sodium sulfite, sodium dithionite, zinc in glacial acetic acid, titanium (III) chloride and many other reducing agents. 6. RESTORATION OF CARBOXYLIC ACIDS AND THEIR DERIVATIVES Carboxylic acids Reduction of the carboxyl group is possible to alcohols and hydrocarbons. Since aldehydes are reduced much faster than acids, they are absent in the final reaction products. In many cases, the reduction of carboxylic acids is difficult. Therefore, it is recommended to convert them into esters or acid chlorides, which are reduced much more easily. Thus, the ability to reduce carboxylic acids and their derivatives varies in the series: RCOO-< RCOOH < RCONR1 < RCN < RCOOR1 < RCOHal 51 Металлические катализаторы гидрирования малоэффективны при восстановлении карбоксильной группы. Вместо них успешно применяют оксидные катализаторы (катализаторы Адкинса), обладающие селективной адсорбционной способностью к кислородсодержащим соединениям. Процесс проводят при высоких температурах 100-300оС и высоком давлении 200-300 атм. Этот метод имеет значение в промышленности для получения высших первичных спиртов с прямой углеродной цепью, а в лаборатории их восстановление чаще всего осуществляют другим путем. При гидрировании карбоновых кислот образующиеся спирты дают сложные эфиры, восстановление которых протекает гораздо легче. 2 H2 R COOH -H2O R CO O H R CH2 OH - H2 O R COOCH2R 2 H2 2 R CH2 OH В практическом отношении такой процесс имеет существенное преимущество, так как устраняется стадия получения сложного эфира. Непредельные карбоновые кислоты и их эфиры можно гидрировать по трём направлениям: 1. по двойной углерод – углеродной связи с образованием предельных кислот; 2. по карбоксильной группе с сохранением двойной связи (получение непредельных спиртов); 3. по обеим функциональным группам с получением предельных спиртов. H2 R CH CH R C H2 C H2 (C H2)n C O O H 2 H2 -H2O (C H2)n C O O H R (C H2)n+2 C H2O H 2 H2 - H O 2 R CH 52 CH (C H2)n C H2 O H H2 Ароматические карбоновые кислоты можно восстановить до соответствующих спиртов или до карбоновых кислот циклогексанового ряда: 2 Н2 . CH2OH CuO Cr2O3, 250 o C COOH 3 H2 COOH Ni, 160 o C Ароматическое кольцо бензойных кислот гидрируется значительно труднее, чем ядро бензола или фенола. Наиболее часто в лабораторной практике для восстановления карбоксильной группы применяют алюмогидрид лития. Восстановление идет в более жестких условиях, по сравнению с восстановлением альдегидов и кетонов. Обычно реакцию проводят при кипячении в тетрагидрофуране: CH3 O CH3 o LiAlH 4 , THF, 40 C OH H3 C H3 C CH3 OH CH3 92% Карбоновые кислоты реагируют с алюмогидридом лития согласно следующему уравнению: LiAl(OCH2R)4 + 2 LiAlO2 + 4 H2 4 RCOOH + 3 LiAlH4 LiAl(OCH2R)4 + 4 H2O 4 RCH2OH + LiAl(OH)4 Таким образом, один гидридный эквивалент алюмогидрида лития расходуется на реакцию с активным атомом водорода кислоты и два эквивалента – на восстановление карбоксильной группы в гидроксильную. Причина инертности карбоновых кислот 53 заключается во-первых, в низкой растворимости их литиевых солей в эфире, во-вторых, в пониженной электрофильности углеродного атома карбоксильной группы. Боргидридом натрия карбоновые кислоты не восстанавливаются. Восстановление карбоксильной группы под действием диборана в тетрагидрофуране осуществляется в очень мягких условиях и не затрагивает некоторые функциональные группы (NO2, CN, COOR). Поэтому этот метод в некоторых случаях оказывается предпочтительнее. O2N o 1. B 2 H6 , THF, 20 C CH 2 COOH 2. H2 O, H O2N + CH 2 CH 2 OH 95% В непредельных кислотах алюмогидридом лития двойные связи практически не восстанавливаются. Однако когда двойная связь сопряжена с ароматическим кольцом, она может восстанавливаться: LiAlH4 CH3CH=CH CH=CHCOOH эфир CH3CH=CH-CH=CHCH2OH 92% CH CH CO OH CH2 C H2 C H2O H LiA lH4 эфир 85% коричная кислота гидрокоричный спирт Сложные эфиры Для гидрирования сложных эфиров в спирты, как и для карбоновых кислот, применяют высокотемпературные оксидные 54 катализаторы Адкинса (хромит меди, реже хромит цинка). В промышленности этим способом из жиров и жирных кислот получают высшие спирты, которые далее перерабатывают в моющие средства. Для восстановления сложных эфиров наряду с хромитными катализаторами применяется скелетный никель. В присутствии избытка этого катализатора эфиры гидрируются при температурах 25 – 125оС и давлении 350 атм с выходами не менее 80%. R COOC4H9 2 H2 R CH2OH + C4H9OH Ni Специфично протекает гидрирование бензиловых эфиров карбоновых кислот на палладиевых катализаторах при температуре 30оС и атмосферном давлении. Продуктами реакции являются соответствующая карбоновая кислота и толуол. O R H2 ÑH2 O CH3 o Pd/C, 30 C + RCOOH Гидрирование этилового эфира бензойной кислоты нельзя остановить на стадии образования бензилового спирта, поскольку гидрогенолиз последнего происходит гораздо легче, чем гидрирование сложного эфира. OH COOEt H2, (200 àòì) CH3 H2 ÑuCr 2O4 o ÑuCr 2O4, EtOH, 25 C + H2 O При получении спиртов восстановлением сложных эфиров комплексные гидриды металлов применяются чаще, чем другие восстановители. В тех случаях, когда целью является получение спирта из соответствующей кислоты, целесообразно восстановлению 55 подвергать не саму кислоту, а её метиловый или этиловый эфиры, так как в этом случае требуется меньший гидридный эквивалент. Восстановление сложных эфиров осуществляют в мягких условиях, при комнатной температуре. В качестве растворителя применяют абсолютный диэтиловый эфир или тетрагидрофуран. Предположительно реакция протекает в две стадии. На первой стадии идёт восстановление сложного эфира до полуацеталя соответствующего альдегида, который затем восстанавливается до первичного спирта. Выходы спиртов обычно высокие: O R CH2 O LiAlH 4 ýôèð CH3 R CH2 CH2 OH Циклические сложные эфиры – лактоны – при восстановлении алюмогидридом лития образуют диолы: O O LiAlH4, эфир H3O + HOCH2CH2CH2CH2OH 83% Боргидрид натрия восстанавливает лишь сложные эфиры фенолов, причём особенно хорошо в тех случаях, когда в ароматическом ядре содержатся электроноакцепторные группы. С другими сложными эфирами взаимодействие боргидрида натрия протекает слишком медленно. В присутствии избытка трехфтористого бора комплексные гидриды металлов восстанавливают сложные эфиры в простые, например: O R O NaBH4 + BF3 диглим, THF Аналогично идет реакция с лактоном: 56 R O 70% O O NaBH4 + BF3 диглим, THF O Сложные эфиры могут быть восстановлены до альдегидов при использовании реагента, обладающего высокой селективностью. Таким реагентом является ДИБАЛ-Н. Для того, чтобы предотвратить дальнейшее восстановление альдегида до первичного спирта, реакцию проводят при температуре -60, -78оС в растворе толуола и инертной атмосфере. H3C H3C CHCOOCH2CH3 ДИБАЛ-Н, толуол, -78 оС Н3О H3C + CHC H3C О Н 79% Фениловые эфиры карбоновых кислот можно восстановить до альдегидов таким мягким восстановителем, как трис(третбутокси)алюмогидрид лития (LTBA): O R O O LiAlH(O-t-Bu)3 R H Восстановление сложных эфиров можно проводить действием металлического натрия в абсолютном этаноле по методу Буво – Блана: RCOOCH2CH3 + 4 Na + 3 CH3CH2OH → RCH2OH + 4СH3CH2ONa Для восстановления по Буво-Блану в лаборатории применяют также изопропанол и циклогексанол. Этот метод дает особенно хорошие результаты при восстановлении эфиров алифатических 57 карбоновых кислот и имеет также промышленное значение для получения непредельных спиртов. В противоположность каталитическому гидрированию при восстановлении по Буво-Блану не затрагиваются двойные связи. Ангидриды и галогенангидриды карбоновых кислот Восстановление ангидридов карбоновых кислот протекает труднее. Реакция идет с выделением СО2: O H3C C O H3C H2 Cd, 280oC C O C CH3 + CO2 CH3 O уксусный ангидрид ацетон При использовании алюмогидрида лития восстановление обычно приводит к превращению ангидридов кислот в первичные спирты: O R O R 1. LiAlH4 2. H2O 2 R CH2 OH O На практике чаще используют восстановление циклических ангидридов дикарбоновых кислот, которые в зависимости от условий могут давать гликоли или лактоны. Так, комплексные гидриды металлов восстанавливают фталевый ангидрид до фталилового спирта (c, d). В других условиях (при этом, избегая избытка комплексных гидридов) удается восстановить фталевый ангидрид до фталида (a, b): 58 O a,b O O O O C H2O H c,d C H2O H а- NaBH4, ДМФА, 0-25оС, выход 97%; b - LiBHEt3, THF, 0oC, выход 76%; c - LiAlH4, эфир, 35оС, выход 87%; d - NaAlH2(OCH2CH2OCH3)2, PhH, 80оС, выход 88%. Из производных карбоновых кислот хлорангидриды относятся к наиболее легко восстанавливаемым соединениям. Каталитическое восстановление водородом хлорангидридов карбоновых кислот приводит к альдегидам (реакция Розенмунда): O R O H2 C R Pd/C Cl + HCl C H В качестве катализатора обычно используют палладий на носителе (BaSO4, CaCO3, BaCO3, уголь, асбест). Легкость гидрогенолиза связи С-Cl при восстановлении хлорангидридов кислот по Розенмунду можно продемонстрировать на следующем примере: O O H2 Cl Pd/BaSO 4 + S 8 /õèíîëèí H Серу и хинолин добавляют с целью сделать катализатор менее активным. Следует отметить, что гидрогенолиз связи С-Cl идет 59 намного легче, чем восстановление карбонильной группы в альдегиде. Это достигается за счет снижения каталитической активности катализатора добавлением каталитических «ядов» (ртуть, сера, амины). Эти соединения образуют достаточно прочные связи с поверхностью катализатора, закрывая его активные центры. Восстановление хлорангидридов карбоновых кислот алюмогидридом лития до первичных спиртов протекает по следующей схеме: O 1. LiAlH4 Cl 2. H2O R R CH2-OH Методы восстановления других производных карбоновых кислот амидов и нитрилов рассматриваются в следующем разделе «Восстановление азотсодержащих соединений». 7. ВОССТАНОВЛЕНИЕ АЗОТСОДЕРЖАЩИХ СОЕДИНЕНИЙ Восстановление соединений, содержащих группы C=N, CN, NO2, N3, N2+, N=N, N=O, N-OH часто используется в лабораторной практике. В промышленности восстановление азотсодержащих соединений проводится главным образом для получения аминов, широко применяемых в качестве основного химического сырья. Для восстановления используются как водород в присутствии катализаторов, так и другие восстановители: комплексные гидриды металлов, щелочные металлы в спиртах, железо, цинк, олово, различные соли. Амины. 60 Амины бензильного типа легко подвергаются гидрогенолизу на таких катализаторах, как палладий на угле или никель Ренея, например: CH3 N CH3 CH3 H2 Ni Дезаминирование* четвертичных аммониевых проводить действием амальгамы натрия: C H3 + C H2N CH3 I H2O, 100 o C C H3 можно C H3 5% Na/Hg C H3 C H3 солей C H3 C H3 Замещение аминогруппы водородом в алифатических аминах применяется редко. Его можно провести обработкой соответствующего тозиламина О-гидроксиламинсульфокислотой в щелочной среде. RNH2 TsCl RNHTs NH2OSO3H водный NaOH RH + N2 _____________________________________________________________________ Дезаминирование* - удаление аминогруппы из молекул органических соединений, сопровождающееся замещением аминогруппы на другую группу или образованием кратной связи. 61 В лабораторной практике дезаминирование используется в тех случаях, когда амино- или диалкиламиногруппа не должна присутствовать в конечном продукте реакции, но необходима на промежуточных стадиях. Дезаминирование ароматических первичных аминов, как правило, проводят через стадию диазотирования с последующей обработкой иона диазония фосфорноватистой кислотой: COOH COOH COOH Br2 Br Br NH2 HNO2 Br COOH Br H3PO2 Br Br + N2 NH2 Br Br Br Нитросоединения Среди групп, содержащих азот, легче всего восстанавливается нитрогруппа. Для гидрирования алифатических нитросоединений применяют малоактивные катализаторы, главным образом медь и железосодержащие. Используя скелетный никель, гидрирование лучше проводить при низких температурах. Нитросоединения в присутствии никеля Ренея, активированного небольшим количеством гидроксида натрия, восстанавливаются с высоким выходом (98 - 99%) до аминов. R H2 NO 2 R NH2 Ni, NaOH Нитроалканы восстанавливают до алкиламинов комплексными гидридами металлов, железом или цинком в кислой среде, гидразином или серосодержащими восстановителями (Na2S, Na2S2O4). Восстановление нитроалканов алюмогидридом лития идет по следующей схеме: R NO 2 1. LiAlH 4 R 2. H 2O 62 NH2 + LiAl(OH) 4 Например, 2-нитробутан восстанавливается до 2-аминобутана с выходом 85%. NO 2 NH2 LiAlH 4 H3C CH3 H3C CH3 ýôèð Наибольшее распространение имеет восстановление нитроаренов. Каталитическое гидрирование ароматических нитросоединений имеет широкое промышленное применение (получение анилина, ароматических ди- и полиаминов). Оно проводится при 200-300оС на медьсодержащем катализаторе. N O2 o 3 H2, 200-300 C + щС щщ C u / A l2O 3 N H2 + 2 2 H2O При использовании таких катализаторов, как платина, палладий, никель, основная реакция (восстановление нитрогруппы) сопровождается гидрированием ароматического ядра, а также частичным отщеплением аминогруппы. Для восстановления ароматических нитросоединений чаще всего применяют металлы (олово, цинк, железные опилки) и соли металлов в присутствии кислот и водных растворов, например: 4 ArNO2 + 9 Fe + 4 H2O → 4 ArNH2 + 3 Fe3O4 ArNO2 + 3 SnCl2 + 6 HCl → ArNH2 + 3 SnCl4 + 2 H2O Восстановление осуществляется через ряд последовательно протекающих реакций. Во всех реакциях процесс восстановления 63 начинается с переноса электрона от восстановителя к молекуле нитросоединения. На ход реакции и природу конечного продукта значительное влияние оказывают рН среды и природа восстановителя. Нитросоединение прежде всего восстанавливается до нитрозосоединения, далее - в замещенный гидроксиламин. O H2 + N - N O - H2O O H2 нитрозобензол H2 NH OH NH2 - H2O фенилгидроксиламин При восстановлении металлом продуктом является первичный амин: в кислой среде конечным NH2 NO 2 9 Fe, 4 H2O 4 4 HCl + 3 Fe3O4 В нейтральной среде например, при взаимодействии нитробензола с цинковой пылью в водном растворе хлорида аммония, процесс восстановления может быть остановлен на стадии образования фенилгидроксиламина. NO2 NHOH Zn, NH4Cl (водн.) 65oC Наконец, у ароматических нитросоединений в щелочной среде процесс восстановления нитрозосоединения, а также гидроксиламина замедляется настолько сильно, что начинает преобладать другая реакция. Свободный арилгидроксиламин обладает высокой нуклеофильностью и поэтому может легко реагировать с арилнитрозопроизводным. Это приводит к азоксисоединениям, 64 которые могут быть гидразосоединений. далее восстановлены до азо- и NO NO 2 íèòðîçîáåíçîë HO + N N - O àçîêñèáåíçîë NHOH ôåíèëãèäðîêñèëàìèí N N àçîáåíçîë NH NH ãèäðàçîáåíçîë Каждое из этих производных азобензола в кислой среде легко восстанавливается до анилина. Амиды Амиды гидрируются в амины на хромите меди или никелевом катализаторе при температуре 210 - 300оС и давлении 100 - 350 атм: H O N H3C H 2 H2 o H Ni, 250 C ацетамид H этиламин 65 + H3C CH2 N H2O H O H 2 H2 N o CH3 H3C Ni, 250 C CH3 o CH3 H3C CH3 CH3 2 H2 N H2O метилэтиламин N-метилацетамид O + H3C CH2 N + H3C CH2 N Ni, 250 C H2O CH3 диметилэтиламин N,N-диметилацетамид N-Моно- и N,N-дизамещенные амиды в аналогичных условиях дают соответственно вторичные и третичные амины. Амиды карбоновых кислот с помощью алюмогидрида лития можно превратить в соединения трех типов: альдегиды, амины или спирты. При этом все реакции проходят через стадию образования полуаминаля соответствующего альдегида: H2O RCHO + R"2NH O-Al H3Li+ RCONR"2 LiAlH4 LiAlH4 RCHNR"2 RCH2NR"2 1. LiAlH4 2. H2O RCH2OH + R"2NH Полное восстановление амидов до аминов используется наиболее часто. На практике для восстановления амидов до аминов следует применять избыток LiА1Н4. N,N-Дизамещенные амиды уже при 25 - 30%-ном избытке LiА1Н4 восстанавливаются до аминов количественно и быстро. N-Монозамещенные амиды следует длительное время (12 - 20 ч) кипятить с 30-40%-ным избытком LiА1Н4. Возможность восстановления амидов с образованием альдегидов зависит от структуры амида, а также от условий реакции. Иногда 66 бывает достаточно смешать реагенты в обратном порядке при низкой температуре или использовать стехиометрическое количество LiА1Н4. Нитрилы Нитрилы восстанавливаются труднее, чем нитросоединения. Гидрирование нитрилов на металлических катализаторах (никель Ренея, кобальт, платина, палладий, медь и др.) идет до первичных аминов. H2 R C N o Pt, 25 C, 1-3 àòì R C N H H2 R CH2 NH2 H При гидрировании нитрилов в качестве побочных продуктов очень часто образуются вторичные и третичные амины. Восстановление нитрилов до аминов имеет практическое значение для тех случаев, когда нитрил дешевле и доступнее, чем соответствующие хлорпроизводные или спирты. В результате восстановления нитрилов алюмогидридом лития можно получить либо амин, либо альдегид. Полагают, что промежуточным продуктом восстановления является имин (RCH=NH) и, следовательно, если остановить реакцию на этой стадии, то после гидролиза получается альдегид; дальнейшее восстановление имина даст первичный амин: 2 LiAlH 4 4 R C ... H2O ... H2O 4 R CH2 NH2 N O LiAlH 4 4 R C H 67 Таким образом, теоретически на полное восстановление 1 моль нитрила в амин расходуется 0,5 моль LiА1Н4. Однако многие нитрилы требуют для восстановления большее количество реагента. Так, для полного восстановления нитрилов до первичных аминов рекомендуется применять не менее 200%-ного избытка LiА1Н4 и, кроме того, проводить процесс при низких температурах, так как при более high temperatures Secondary amines may form. Aromatic and aliphatic nitriles can easily be converted to aldehydes by the action of LiA1H4, depending on the reaction conditions and the order of addition of reagents. When nitriles are reduced with sodium in ethanol, amines are formed: 4 Na H3C C N H3C CH2 EtOH acetonitrile NH2 + 4 CH 3CH 2ONa ethylamine Under the influence of tin chloride in a hydrochloric acid environment, products of incomplete reduction are formed - aldimines: SnCl 2, 2 HCl H3 C C N H3 C CH NH + SnCl 4 Oximes Reduction of oximes is the most convenient way to go from aldehydes and ketones to amines. Oximes are easily reduced by catalytic hydrogenation over platinum or palladium, whereas when using skeletal nickel a temperature of ~100°C is required. In laboratory practice, lithium aluminum hydride is more often used to reduce oximes: 68 R N OH R R LiAlH4 NH2 ýôèð R Thus, the reduction of 1 mol of oxime requires 0.75 mol of LiA1H4, while 0.25 mol of hydride is spent on the reaction with active hydrogen of the oxime. The reaction in question is an indirect method for obtaining primary amines from the corresponding aldehydes and ketones. However, yields of primary amines are often low due to the possibility of side processes. In particular, aryl ketoximes form significant amounts of secondary amines. Azomethines Reduction of azomethines (Schiff bases) to secondary amines is carried out by catalytic hydrogenation over platinum or palladium: R CH N 1 R H2 R Kt CH2 NH 1 R Imines, Schiff bases and other compounds containing a C=N bond are also reduced by the action of LiA1H4 and NaBH4. Diazonium salts The reduction of diazonium salts, depending on the conditions and the nature of the reducing agent, can proceed with the formation of phenylhydrazines or aromatic hydrocarbons. It is more convenient to reduce diazonium salts with an aqueous solution of 69 hypophosphorous acid H3PO2. This technique is often used to remove an amino group (see section Amines (deamination)). + N N Cl - H3PO2, H2O + o 10-25 C N2 + HCl + H3PO3 The reduction of diazonium salts to hydrocarbons can be carried out by the action of formaldehyde in an alkaline medium: + N N Cl - CH2O + N2 + HCl + H2O + HCOONa NaOH The diazo group can be replaced by hydrogen by the action of ethanol when heated. However, the process occurs with the formation of significant quantities of a by-product - phenetol. + N N Cl - O CH3 O C2H5OH + + o t C N2 + HCl + H3 C H conditions Reduction of aryldiazonium tetrafluoroborates can be carried out by the action of sodium borohydride at a temperature not exceeding 0°C: + N N BF4 N aBH4 MeO H or DMF A 70 A convenient method for the preparation of arylhydrazines in laboratory conditions is the reduction of diazonium salts with tin(II) chloride. Reduction is carried out in hydrochloric acid at a temperature of 0–10°C. + N N Cl - + NH NH3 Cl SnCl 2 - NH NH2 NaOH HCl H 2O + + NaCl H 2O additions The main industrial method for the reduction of diazonium salts is the sulfite-bisulfite method. Sodium sulfite attaches at the triple bond of the diazo group, and then sodium bisulfite at the double bond of sodium benzenediazosulfonate. + N N Cl Na2SO3 N N SO3Na + NaCl H N N SO3Na HCl NaHSO3 . NH NH2 HCl SO3Na By heating the disodium salt of N,N1-phenylhydrazine disulfonic acid in concentrated hydrochloric acid, phenylhydrazine hydrochloride is obtained. Other substituted phenylhydrazines are prepared using a similar scheme. Azides Azides can be reduced to primary amines by hydrogen over a metal catalyst or lithium aluminum hydride: 71 + N H3C HC N - N H2N H2 COOC2H5 H3C CH COOC2H5 Pt ethyl α-azidopropionate ethyl α-aminopropionate Aliphatic and aromatic azides are reduced with lithium aluminum hydride according to the following general equation: 4 RN3 + LiAlH4 → LiAl(NHR)4 + 4 N2 In practice, an excess of 1.2-1.5 mol of LiAlH4 per 1 mol of azide is used and the reduction is carried out in boiling ether for several hours. R N + N LiAlH4 - N R ýôèð NH2 R=Alk, Ar Azides are not reduced by sodium borohydride. A convenient method for the reduction of azides to primary amines is the reaction with triphenylphosphine, proceeding through the formation of the intermediate phosphinimine, which, under the influence of HBr in acetic acid, is saponified to form the amine and triphenylphosphine oxide: P + R HBr N P -N 2 + N - N R NH2 + P 72 O N R CH 3COOH Azo compounds Reduction of the N=N bond of azo compounds easily occurs under hydrogenation conditions: N H2 N NH o H2 NH Pd/C, 20 C azobenzene hydrazobenzene NH2 2 8. RESTORATION OF SULFUR CONTAINING COMPOUNDS Reduction of aliphatic and aromatic sulfonic acids is carried out with metals in an acidic environment. In this case, thioalcohols (thiols) or thiophenols are formed: O R S Zn O R SH HCl OH R=Alk, Ph Sulfoxides, unlike sulfonic acids, are more accessible to nucleophilic attack, so they can be successfully reduced both by zinc in hydrochloric acid and by complex metal hydrides to sulfides (thioethers): O Zn, 2 HCl S H3C CH3 S H3C CH3 73 + ZnCl2 + H2O Sulfones are much more stable than sulfoxides. They are reduced by the action of lithium aluminum hydride at a temperature of 100°C for a long time. The reduction products are sulfides: O O 2 LiAlH 4 2 S H3C CH3 + S H3C CH3 LiAlO 2 + 2 H2O Mercaptans (thiols), sulfides, disulfides, sulfoxides, sulfones can be reduced to the corresponding hydrocarbons by the method of reductive desulfurization (desulfurization). Reduction is typically carried out with hydrogen over Raney nickel and other catalysts. H2 H3C CH2 SH H3 C 2 H2 CH3 S + H3C CH3 Kt H2S 2 CH4 + H 2S 2 CH4 + 2 H2S + H 2S Kt H3C S S 3 H2 CH3 Kt O 3 H2 S H3 C CH3 O O S H3C CH3 2 CH4 Kt 4 H2 2 CH4 Kt 74 + H 2S + + H2 O 2 H2O Heterocyclic compounds, for example thiophene, benzothiazole, thioindium dyes, etc., are also capable of desulfurization. The ability of thiophene derivatives to desulfurize is used for the synthesis of the corresponding aliphatic compounds. Reduction is carried out on Raney nickel in ethanol. H2 S R Kt H3C R + H 2S The reduction of sulfur-containing compounds to hydrocarbons in petroleum fractions is widely used in industry (hydrotreating process). Disulfides are easily reduced to thiols by zinc in acetic acid (old method) or by a solution of an alkali metal in liquid ammonia: R S S R 1)Na; liquid NH3; -330C 2) H2O; NH4Cl 2 R SH 9. PREPARATION OF REDUCING AGENTS AND REDUCTION CATALYSTS Hydrazine hydrate ·SO4 + 2 KOH  N2H4H2O + K2SO4 + H2O Reagents: hydrazine sulfate – 50 g (0.38 mol); Potassium hydroxide – 50 g (0.89 mol). 75 Mix 50 g of dry hydrazine sulfate with the same amount of powdered KOH, add 2.5 ml of water and distill the resulting hydrazine hydrate with a downward condenser. At first, the distillation is carried out with low heat, but towards the end of the reaction, the mixture must be heated strongly to complete it. Hydrazine hydrate, which still contains water, is purified by fractional distillation. Pure hydrazine hydrate is distilled in the range of 117-119°C. Hydrazine, anhydrous N2H4 N2H4H2O  N2H4 +H2O Oily, highly fuming liquid. Corrodes cork, rubber and other organic substances. It hardens at 0°C and boils at 113.5°C. It can be stored in bottles with ground-in stoppers for an indefinitely long time. Flammable substance. Miscible with water and alcohols. Explodes when mixed with air when heated. Reagents: hydrazine hydrate – 20 g, 19.4 ml (0.4 mol); sodium hydroxide – 20 g (0.5 mol). Place 20 g of hydrazine hydrate and 20 g of NaOH granules into a fractional distillation flask with a ground stopper and a ground thermometer. The flask is heated very slowly in an oil bath so that the hydrazine begins to boil only after 2 hours. By this time, all of the NaOH should have already dissolved in the liquid. The temperature of the oil bath should be ~120°C. Once distillation has begun, the flask is continued to be heated slowly until the temperature of the oil bath reaches ~150°C. In this case, pure anhydrous hydrazine is distilled off. 76 Aluminum isopropylate Al(OCH(CH3)2)3 Al + 3 (CH3)2CHOH  Al(OCH(CH3)2)3 + 3/2 H2 Reagents: aluminum – 27 g (1 gram of atom); isopropyl alcohol – 300 ml (3.9 mol); sublimate (mercuric chloride, HgCl2) – 0.5 g; carbon tetrachloride – 2 ml. In a liter flask with an effective reflux condenser, protected by a calcium chloride tube, mix 27 g of aluminum foil with 300 ml of anhydrous isopropyl alcohol and 0.5 g of mercuric chloride. The mixture is then heated to reflux. As soon as the mixture begins to boil, add 2 ml of carbon tetrachloride through the refrigerator and heat until hydrogen evolution begins. After this, the heating is stopped (in some cases it may even be necessary to resort to cooling). When the main, violent stage of the reaction is over, the mixture is boiled again until the aluminum is completely dissolved (6 - 12 hours). Then the solvent is distilled off and the residue is distilled under reduced pressure using an air cooler. The resulting product usually hardens only after 1–2 days. The yield is about 90 - 95% of theoretical. Bp 130 – 140°C / 7 mm Hg, melting point 118°C. To carry out the Meerwein–Ponndorf–Verley reduction, a 1 M solution of aluminum isopropylate in anhydrous isopropyl alcohol is often used. This solution can be stored in a bottle carefully closed with a glass stopper; The outside of the cork is filled with paraffin. 77 Triethylsilane HSiCl3 + 3 CH3CH2MgBr  (CH3CH2)3SiH a) Preparation of the Grignard reagent. C2H5Br + Mg → C2H5MgBr Reagents: magnesium – 19.1 g (0.78 gram atom); ethyl bromide – 100 g (0.8 mol); absolute diethyl ether – 400 ml. In a three-neck flask with a capacity of 2 liters, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel with calcium chloride tubes, place 19.1 g of magnesium shavings and a small amount of ether (40-45 ml). Then add 1-2 ml of ethyl bromide. After 10-15 minutes, the solution becomes cloudy and the ether warms up. If the reaction does not start, then add a few crystals of iodine or 0.5 ml of 1,2-dibromoethane to the reaction mixture and slightly warm the flask with warm water. After the reaction has begun, add dropwise with stirring the remaining amount of ethyl bromide (total 0.8 mol), dissolved in approximately 320-360 ml of ether. The reagent is added at such a rate that the mixture boils moderately. After adding the entire amount of ethyl bromide, the reaction mixture is gently heated on a hotplate for 30 minutes until the magnesium is completely dissolved. b) Preparation of triethylsilane. Reagents: trichlorosilane – 27.0 g (0.2 mol); ethylmagnesium bromide – 0.8 mol; diethyl ether – 500 ml; 3% hydrochloric acid. To a freshly prepared solution of 0.8 mol of ethylmagnesium bromide in 400 ml of diethyl ether, 27.0 g (0.2 mol) of trichlorosilane in 100 ml of diethyl ether is added with stirring and cooling. The reaction mass is heated for 5 hours, then treated with 250 ml of 3% hydrochloric acid. Organic layer 78 is separated, dried with sodium sulfate, the ether is evaporated, and the product is distilled at a temperature of 107 - 108 ° C. Yield 20.8 g (90% of theoretical), n D20 1.4130. Sodium amalgam Reagents: sodium – 6.9 g (0.3 gram atom); mercury – 340 g (1.69 grams of atom). Place 6.9 g of neatly cut sodium into pieces (for amalgam containing 2% wt. sodium) or 10 g (for amalgam containing 3% wt. sodium) into a round-bottomed flask with a capacity of 250 ml. Tubes for nitrogen input and output are passed through two side throats. A dropping funnel with 340 g (25 ml) of mercury is inserted into the middle throat. After thoroughly filling the flask with nitrogen, 10 ml of mercury is added to the sodium and the flask is gently heated over an open flame until the reaction begins. Then the remaining amount of mercury is slowly poured in, while it is enough to only slightly warm the flask. When all the mercury has been transferred to the flask, the still hot molten amalgam is poured onto a clean tile and broken into pieces (under draft!) while it is still warm and brittle. If sodium is taken at 1% by weight, then a liquid amalgam is obtained. Zinc amalgam Reagents: zinc – 15 g (0.22 grams of atom); mercury chloride (HgCl2) – 2.5 g (0.009 mol); water – 50 ml. Place 15 g of zinc in a round-bottomed flask with a capacity of 250 ml, add a solution of 2.5 g of mercury chloride in 50 ml of water and leave to stand for 1 hour with frequent stirring. Then the liquid is drained, and the zinc is washed several times with clean water. 79 Skeletal nickel catalyst NiAl2 + 6 NaOH + 6 H2O  Ni + 2 Na3 + 3 H2 Caution! The reaction produces hydrogen and the work should be carried out in a well-functioning fume hood. The catalyst is pyrophoric and spontaneously ignites in air. Therefore, the catalyst should be stored under a layer of alcohol. Reagents: nickel-aluminum alloy – 10 g; sodium hydroxide – 16 g (0.4 mol). 10 g of nickel-aluminum alloy and 100 ml of distilled water are placed in a glass with a capacity of 1 liter. Then add solid sodium hydroxide at such a rate that foaming does not occur too violently. The reaction begins vigorously after a certain induction period, so caution should be exercised at first. When further addition of sodium hydroxide no longer leads to noticeable boiling (up to this point approximately 16 g must be added), the mixture is kept for 10 minutes at room temperature and then 30 minutes in a water bath at 70 ° C. After the specified time, the liquid located on top of the nickel that has settled to the bottom of the glass is thoroughly decanted and the catalyst is washed with distilled water, stirring and draining the water from the settled sediment. Washing is carried out until a neutral reaction for phenolphthalein is achieved. In the same way, the water is then replaced with alcohol (20 - 30 ml). The catalyst is stored in a glass container under a layer of alcohol. Although the catalyst can be stored in this way for some time, it is more advisable to prepare it immediately before use (in the amount required for each specific synthesis), avoiding a noticeable decrease in its activity during storage. The activity of the 80 catalyst can be checked by placing a few grains of it on a sheet of paper: after 1 - 2 minutes, spontaneous combustion of the catalyst can be observed. Palladium sorbed on carbon PdCl 2 H2 Pd/C carbon Reagents: palladium dichloride – 0.5 g (0.03 mol); activated carbon – 4 g; hydrogen. In a hydrogenation vessel, an aqueous solution of 0.5 g of palladium dichloride is added to 4 g of activated carbon. Restoration is carried out using the installation shown in section 10, Fig. 1. After the absorption of hydrogen is completed, the catalyst is filtered off, washed with water, alcohol and, finally, ether. The resulting catalyst contains 7% palladium supported on coal. Preparation of platinum black by the Willstetter method H2PtCl6 + 8 KOH + 2 CH2O  Pt + 2 HCOOK + 6 KCl + 6 H2O Reagents: hydroplatinic acid – 5 g (0.012 mol); formalin 40% – 15 ml; potassium hydroxide 50% aqueous solution – 28 ml. In a conical flask containing 5 g of hydroplatinic acid dissolved in 10 ml of water, add 2 - 3 drops of hydrochloric acid and 15 ml of a 40% solution of 81 formaldehyde. The resulting mixture is cooled to –10°C (ice with salt) and, making sure that the temperature does not rise above 5°C, 28 ml of a 50% potassium hydroxide solution is carefully added dropwise. The mixture is heated with stirring for 30 minutes at a temperature of 55 - 60°C. The precipitated platinum black is washed several times with water. Then quickly filter on a Buchner funnel, making sure that the platinum is under a layer of water. Then squeeze between sheets of filter paper and place in a vacuum desiccator. After 2 - 3 days, the desiccator is filled with carbon dioxide, in the atmosphere of which the catalyst is stored until use. Palladium black is prepared in the same way. Yield about 1.8 g (75%). Before use, the catalyst must be activated with air or oxygen by shaking it in a solvent (ethyl alcohol, ethyl acetate, etc.). Platinum and palladium black must not be brought into contact with explosive mixtures such as air-methanol, air-benzene or air-hydrogen. Preparation of platinum dioxide by the Adams method H2PtCl6 + 6 NaNO3  Pt(NO3)4 + 6 NaCl + HNO3 Pt(NO3)4  PtO2 + 4 NO2 + O2 PtO2 + H2O  PtO2H2O Reagents: chloroplatinic acid – 3.5 g ( 0.0086 mol); sodium nitrate – 35 g (0.41 mol). In a porcelain crucible (or in a Pyrex glass glass), 3.5 g of hydroplatinic acid is dissolved in 10 ml of water and 35 g of crystalline sodium nitrate is added to the solution. The mixture is carefully heated with a burner and, stirring with a glass rod, 82 is evaporated to dryness. After this, the temperature is gradually increased to 350 - 370°C. the mass melts, brown vapors of nitrogen oxides are released (thrust!) and brown platinum oxide is formed. In case of possible foaming of the mass, stirring must be intensified without stopping the heating of the crucible. After 15 - 20 min. The gas emission will decrease significantly after another 15 – 20 minutes. completely stops, heating the crucible should be continued for another 30 minutes. until the reaction mass completely melts. The temperature reaches 500 – 550°C. This temperature is most favorable for obtaining a catalyst with maximum activity. After melting is complete, the mass is allowed to cool and then treated with 50 ml of water. The resulting brown precipitate of platinum oxide, which quickly settles to the bottom of the crucible, after three times decantation in the crucible, is transferred to a funnel, washed on a filter until the nitrate salts are completely removed (sample with diphenylamine), sucked off and dried in a desiccator to constant weight. The resulting platinum oxide (1.5 - 1.65 g), which is a heavy granular brown powder, is used as a starting material to obtain platinum black in the form of a fine suspension. To do this, platinum oxide, located in the solvent used for hydrogenation (ethyl alcohol, ethyl acetate, glacial acetic acid), is reduced with hydrogen at room temperature. 10. EXPERIMENTAL Hydrogenation procedure Laboratory hydrogenation in the liquid phase at atmospheric pressure is carried out in a flask equipped with a Drexel nozzle. Stirring of the reaction mixture is achieved using a magnetic stirrer. Hydrogen enters the reactor from a gas burette (Fig. 1), connected by a rubber hose to equalizing flask 83 (pressure tank). Before hydrogen is supplied to the burette, it is filled with water, the gas line from the burette to the reactor is closed, and the line from the gas meter with hydrogen to the burette is opened. Rice. 1. Installation for catalytic hydrogenation at atmospheric pressure: 1 – gasometer; 2 – three-way valve; 3 – gas cylinder (burette); 4 – equalization flask; 5 – reaction flask with Drexel attachment; 6 magnetic stirrer. Water is displaced from the burette with hydrogen into an equalizing flask, after which the hydrogen reservoir (gasometer) is turned off and the tap on the gas line connecting the burette and the reactor in which the reagents are placed and which is previously “washed” with hydrogen is opened. By lowering the equalizing flask, the water level in it and the burette is equalized and thereby the pressure in the system is established equal to atmospheric pressure. Having measured the initial volume of hydrogen in the burette, hydrogenation begins. 84 Hydrocinnamic acid (3-phenylpropionic acid) O O H2 OH Ni OH Reagents: cinnamic acid – 3.7 g (0.025 mol); Raney nickel – 0.5 g; hydrogen (from a cylinder); ethanol – 20 ml. The work is carried out in a catalytic hydrogenation unit (Fig. 1). A gasometer filled with hydrogen is connected using a three-way valve to a gas cylinder, which is filled with hydrogen. The volume of gas is noted, for which the equalizing flask is installed so that the water level in it is the same as the water level in the cylinder. Then move the three-way valve to the position where the gas cylinder is connected to the reaction flask, and check the installation for leaks. After this, closing the connection between the installation and the flask, add cinnamic acid, ethanol and 0.5 g of Raney nickel. Next, the air is displaced from the reaction flask. To do this, it is connected to a gas cylinder and 200–300 ml of hydrogen is slowly passed through. Hydrogen comes out under the draft through a hose placed on the outlet tube of the Drexel nozzle. After flushing, the system is closed with a plug placed on the outlet tube of the Drexel nozzle, and the three-way valve is moved to the position in which the gas cylinder is connected to the reaction flask. The initial volume of hydrogen in the cylinder is noted and the stirrer is started. Hydrogenation can be considered complete when the calculated amount of hydrogen has been absorbed. The reaction mass is filtered, ethanol is carefully removed using a rotary evaporator. The residue hardens in the cold. The product is purified 85 by recrystallization from dilute hydrochloric acid (approximately 10%). Yield 3.4 g (90% of theoretical). Melt 47 - 49oC. Methylcyclohexane. Reduction of 1-methylcyclohexanol-1 with triethylsilane CH3 CH3 (C 2H5)3SiH OH CF 3COOH Reagents: 1-methylcyclohexanol-1 – 15.1 g (0.13 mol); trifluoroacetic acid – 37.5 ml (0.49 mol); triethylsilane – 30 ml; hexane – 40 ml; 20% sodium hydroxide solution - 120 ml. 30 ml of triethylsilane in 40 ml of hexane are added dropwise to a solution of 15.1 g of 1-methylcyclohexanol-1 in 37.5 ml of trifluoroacetic acid at a temperature not exceeding 25°C. Stir for 1 hour and keep at 45-50°C for 50 hours. Then the reaction mass is cooled, neutralized with 120 ml of a 20% sodium hydroxide solution, boiled for 5 hours, the organic layer is separated and dried with sodium sulfate. Hexane is distilled off, and the residue is distilled, collecting the fraction at a temperature of 100-101°C. Yield: 11.6 g (92% of theory). Boiling point 101°C, n20D 1.4220. Benzyl alcohol and benzoic acid. Reduction of benzaldehyde (Cannizzaro reaction). Method A. O H OH KOH O + 2 86 - + OK Reagents: benzaldehyde – 20 g, 19.2 ml (0.18 mol); potassium hydroxide – 17 g (0.3 mol); methylene chloride. Place 20 g of freshly distilled benzaldehyde and a cooled solution of potassium hydroxide (17 g in 10 ml of water) into a 100 ml flask. The mixture is shaken until a stable emulsion is formed (10-20 min) and left in a closed flask for a day. 10 ml of water is added to the resulting mass and benzyl alcohol is extracted from the resulting solution with methylene chloride 2-3 times 20 ml each. The extracts are combined together and washed with 10 ml of a 40% solution of sodium hydrosulfite, then with an aqueous solution of soda, and dried over anhydrous Na2SO4. First, methylene chloride is distilled off in a water bath, then the water cooler is replaced with an air cooler and benzyl alcohol is distilled. The boiling point of alcohol is 206°C. The yield of benzyl alcohol is 8.2 g (84% of theoretical). The aqueous-alkaline solution remaining after extraction with benzyl alcohol ether is acidified with hydrochloric acid. The precipitated benzoic acid is filtered off and recrystallized from water. The yield of benzoic acid is about 6.9 g (60% of theoretical). Benzyl alcohol. Reduction of benzaldehyde (Cannizzaro cross reaction). Method B. O H OH H + OH O H 87 - + HCOOH Reagents: benzaldehyde – 20 g, 19.2 ml (0.18 mol); formalin (40%) – 40 ml; sodium hydroxide – 16 g (0.4 mol); sodium hydrosulfite. 19.2 ml of benzaldehyde, 50 ml of water and 40 ml of formaldehyde are poured into a flask equipped with a reflux condenser. With constant stirring, add a solution of sodium hydroxide (16 g of NaOH in 24 ml of water) and heat the reaction mixture to 700C. Then the flask is capped and left to stand for 24 hours. The liquid separates into two layers. Benzyl alcohol is separated, washed with sodium hydrogen sulfite and water, dried over anhydrous Na2SO4 and distilled. Boiling point – 2060C. Yield 11.6 g (59% of theoretical). Butanol-2. Reduction of methyl ethyl ketone with sodium in ether O H3C CH3 OH Na H3C CH3 Reagents: methyl ethyl ketone – 8.5 g (0.12 mol); metal – 8 g (0.35 grams of atom); ether – 60 ml; water. sodium Place 8.5 g of methyl ethyl ketone, 16 ml of water and 15 ml of ether in a two-neck flask with a reflux condenser. While cooling the flask with ice water and shaking continuously, 8 g of sodium is gradually added to it in small pieces (pieces are cut off with a scalpel on filter paper - see precautions). When half of the total sodium has been added, larger pieces of sodium can be introduced and another 8 ml of water can be added. When all the sodium has reacted, the upper layer is separated in a separatory funnel, and the lower (aqueous) layer is extracted once with 40 ml of ether. The ethereal extracts are combined, washed once with water, dried over MgSO4, the ether is distilled off and the fraction with a boiling point of 95-1010C is collected. Yield 6.2 g (70% of theoretical). 1-Phenylethanol. Reduction of acetophenone in the presence of aluminum isopropylate O HO CH3 CH3 O i-PrOH + Al(O-i-Pr) 3 H3 C CH3 Reagents: acetophenone – 12.2 g (0.1 mol); aluminum isopropylate – 20.4 g (0.1 mol); isopropyl alcohol – 100 ml; 3 M H2SO4 solution – 200 ml. In a 200 ml flask with a reflux condenser equipped with a calcium chloride tube, mix 20.4 g of aluminum isopropylate in 100 ml of isopropyl alcohol (for the preparation of aluminum isopropylate, see section 9) and 12.2 g of acetophenone. The reaction mixture is boiled for one hour, then the reflux condenser is replaced with a downward condenser and the resulting acetone and isopropyl alcohol are distilled off at a rate of 5 drops/min. The flask with the remaining liquid is cooled. The liquid is gradually poured into 175 ml of a cooled 3 M H2SO4 solution with stirring, the remaining liquid from the flask is washed off with 25 ml of a cooled 3 M H2SO4 solution and added to the bulk. From the resulting mixture, 1-phenylethanol is extracted several times with methylene chloride. Extracts of the product in methylene chloride are dried over anhydrous K2CO3, 89 methylene chloride is distilled off, and the residue is distilled in vacuum. Boiling point – 940C (12 mm Hg. Art.). Yield 8.6 g (71% of theoretical). Ethylbenzene. Reduction of acetophenone according to Clemmensen O CH3 CH3 + 2 Zn + + 4 HCl 2 ZnCl2 + H 2O Reagents: acetophenone - 6 g (0.05 mol); granulated zinc 15 g (0.23 gram atom); mercury chloride – 2.5 g (0.009 mol); concentrated hydrochloric acid – 10 ml; calcium chloride. To amalgamated zinc, prepared from 15 g of zinc and 2.5 g of mercuric chloride according to the method (see section 9), placed in a 250 ml round-bottom flask, add acetophenone and add 30 ml of dilute hydrochloric acid, obtained by mixing 10 ml of concentrated hydrochloric acid with 20 ml of water. The flask is connected to a reflux condenser, heated on a hot plate until the liquid boils vigorously and boiled for 5 hours, adding 7-8 ml of acid every hour. At the end of the reaction, the resulting ethylbenzene (floating on the surface of the liquid in the form of a colorless oil) is quickly distilled off with steam, separated from the water using a separating funnel, dried with calcium chloride and distilled from a small distillation flask with an air cooler. Yield 4 g (75% of theoretical). Type 136.3°C. 90 Cyclohexanol. Reduction of cyclohexanone with sodium borohydride O HO NaBH 4 i-PrOH Reagents: cyclohexanone – 9.8 g (0.1 mol); sodium borohydride – 1.5 g (0.04 mol); isopropanol – 120 ml; hydrochloric acid; methylene chloride; sodium sulfate. Sodium borohydride is gradually added to a solution of 9.8 g of cyclohexanone in isopropyl alcohol at room temperature with stirring. To complete the reaction, the reaction mixture is left overnight. Then dilute hydrochloric acid is carefully added until the evolution of hydrogen stops. The resulting solution is shaken 5 times with small portions of methylene chloride; the extracts are dried with sodium sulfate, the solvent is distilled off. Yield 8 g (80% of theoretical). Type 160°C, n20D 1.4650. N,N-Furfuryldiethylamine. Reductive amination of furfural O O H CH3 + (ÑH3CH 2)2NH + N HCOOH CH3 O 91 + CO 2 + H2 O Reagents: diethylamine - 52 ml (0.5 mol); freshly distilled furfural - 8.3 ml (0.1 mol); formic acid (85%) - 22 ml (0.57 mol); sodium hydroxide; methylene chloride. In a 200 ml three-neck flask equipped with a mechanical stirrer, a dropping funnel and a reflux water condenser, place 22 ml of an 85% formic acid solution. Gradually (over 2.5 - 3 hours) add 52 ml of diethylamine from the dropping funnel. The addition of diethylamine causes a violent reaction. Therefore, the flask with the reaction mixture is cooled in a cold water bath. When the reaction slows down, the reflux condenser is replaced with a downward condenser, and the dropping funnel is replaced with a thermometer and the liquid distilled to 135°C is distilled off. After cooling the reaction mixture to room temperature, 8.3 ml of freshly distilled furfural is added to it. The flask is again connected to reflux and heated in an oil bath for 5 hours at a reaction mixture temperature of 150°C. Then the mixture is cooled to room temperature, 100 ml of water is added to it and poured into a 1 liter round-bottomed flask. While cooling with water, 25 g of solid sodium hydroxide is added in small portions to the reaction mixture and the mixture is distilled with steam. 250 - 270 ml of liquid are distilled off. 25 - 30 g of sodium hydroxide are dissolved in the distillate, and two layers are formed. The upper layer is separated using a separatory funnel, and the lower (aqueous) layer is extracted three times with methylene chloride (15 ml portions). The main reaction product is combined with extracts of methylene chloride and dried with sodium hydroxide. Methylene chloride is distilled off in a water bath and then furfuryldiethylamine, collecting the fraction boiling at 169 - 172 °C. Yield 10.7 g (70% of theoretical). Sylvan. 92 Reduction of furfural according to Kizhner-Wolf NH2 O O N2H4 N neutral H O H o NaOH, t C -N2 CH3 O Reagents: furfural – 25 g (0.26 mol); ethylene glycol – 125 ml; hydrazine hydrate – 15 ml, 15.45 g (0.3 mol); sodium hydroxide – 4 g. In a 250 ml round-bottomed flask, mix freshly distilled furfural with ethylene glycol and gradually add 15 ml of hydrazine hydrate while shaking and cooling with water. In this case, a yellow crystalline precipitate of furfural hydrazone precipitates (sometimes the precipitate does not precipitate, but this does not significantly affect the yield of sylvan). The mixture is left for 15 minutes at room temperature, then NaOH is added, a reflux condenser with a downward condenser is connected to the flask and heated for 45 minutes in an oil bath at 100°C. Then, within 1 hour, the temperature is raised to 145°C, while sylvan and water are distilled off. Silvan is separated from water, dried over NaOH and distilled. Yield 12.8 g (60% of theoretical); Type 63 - 68.5°C; nD20 1.4345. Benzyl alcohol. Reduction of methyl benzoate with lithium aluminum hydride O O OH CH3 1. LiAlH 4 2. HCl 93 Reagents: methyl benzoate - 12.5 g (0.092 mol); lithium aluminum hydride – 2.1 g (0.055 mol); diethyl ether – 50 ml; ethyl acetate – 5 ml; hydrochloric acid (4 M) – 60 ml; sodium sulfate. Lithium aluminum hydride is added in small portions with stirring to 30 ml of dry ether and boiled until most of the aluminum hydride is dissolved. Then a solution of methyl benzoate in 20 ml of ether is added dropwise at a speed that ensures low boiling of the solvent. After stirring and boiling for 30 minutes, add ethyl acetate slowly and then 60 ml of 4 M hydrochloric acid (see Note). The aluminum oxide precipitate is filtered off and washed with a small amount of ether. The organic layer is separated from the aqueous layer using a separatory funnel. Essential extracts are dried with sodium sulfate. The solvent is distilled off. Benzyl alcohol is distilled at 205 - 207°C. Yield 7.9 - 8.5 g (80 - 90% of theoretical). Note. Lithium aluminum hydride for reduction is often taken in a large excess of theory (2–4 times excess), although the need for this is often not confirmed by control experiments. When decomposing a large amount of lithium aluminum hydride, even slowly adding water and stirring must be done very carefully, since the liberated hydrogen can cause violent foaming. Using a 10% solution of NaOH or ammonium chloride is more convenient, since the granular aluminum oxide released is easily filtered. Ethyl acetate is often used to decompose excess lithium aluminum hydride, because in this case, hydrogen is not released and the reduction product (ethanol) does not interfere with the release of the final product. 4 CH3COOC2H5 + LiAlH4 → LiOCH3 + Al(OCH3)3 + 4 C2H5OH The release of the reduction product is often hindered by a bulky gelatinous precipitate of hydroxides, the treatment of which with an excess of acid or alkali 94 leads to an increase in volume and the formation of emulsions. This can be avoided by sequentially adding n ml of water dropwise to the reduced mixture of n g lithium aluminum hydride, then n ml of a 15% NaOH solution and 3 n ml of water (with stirring). This results in the formation of a dry granular precipitate that can be easily filtered and washed. Phenylhydroxylamine. Reduction of nitrobenzene in a neutral environment NO 2 NHOH 2 Zn, NH 4Cl + o 3 H2O, 60 C 2 Zn(OH) 2 Reagents: nitrobenzene - 6 g (0.048 mol); ammonium chloride - 3.5 g; zinc dust - 9 g (0.13 grams of atom); water; sodium chloride. In a 250 ml flask, dissolve ammonium chloride in 60 ml of water and add 6 g of nitrobenzene. The mass is vigorously stirred and 9 g of zinc dust is gradually added over about 20 minutes. In this case, the temperature should not exceed 60 - 65°C. After adding all the zinc dust, the mixture is stirred for another 30 minutes until the end of the reaction - until the smell of nitrobenzene disappears. The warm solution is filtered. The precipitate is washed with 30 ml of hot water. The wash water and filtrate are combined, finely ground sodium chloride is added until saturated and cooled with a mixture of ice and salt for 60 minutes. 95 Phenylhydroxylamine is released in the form of thin light yellow needles. It is filtered and air dried. Recrystallize from benzene or petroleum ether. Yield 2.5 – 3.2 g (up to 60% of theoretical). Melting point 81°C (with decomposition). Hydrazobenzene. Reduction of nitrobenzene in an alkaline environment NO 2 Zn, NaOH 2 NH o NH t C Reagents: nitrobenzene – 6 g (0.048 mol); sodium hydroxide – 10 g (0.25 mol); zinc dust – 17 g (0.26 mol); ethanol. In a two-neck flask with a capacity of 250 ml, equipped with a reflux condenser, place 6 g of nitrobenzene, 25 ml of water, 13 ml of alcohol and 10 g of sodium hydroxide. Mix everything and add zinc dust in small portions through the side throat. After adding the next portion, close the throat with a stopper and shake the device. The color of the solution is first red, then yellow. When the reaction stops, add the next portion of zinc filings. After adding all the zinc dust, 75 ml of alcohol is poured into the flask and the mixture is heated in a water bath to a boil. The solution is cooled in an ice water bath. Hydrazobenzene is released in the form of almost colorless crystals. The crystals are filtered, then washed on a funnel with a small amount of 50% alcohol and dried in a desiccator. 96 Yield 3.4 g (77% of theoretical). Melt 125oC. Aniline. Reduction of nitrobenzene in an acidic environment NH2 NO 2 9 Fe, 4 H2O + 4 4 HCl 3 Fe3O4 Reagents: nitrobenzene – 4 g (0.03 mol); hydrochloric acid 3% – 15 ml; iron filings – 7 g; sodium hydroxide – 0.4 g; sodium chloride. 7 g of iron filings, 15 ml of 3% hydrochloric acid and 4 g of nitrobenzene are placed in a 250 ml flask equipped with a reflux condenser. The reaction mass is brought to a boil and boiled for 4-4.5 hours until the smell of nitrobenzene disappears. After the reduction is complete, 0.4 g of sodium hydroxide is added to the reaction mixture and the aniline is distilled off with steam. Sodium chloride is added to the distillate, the product is extracted with methylene chloride. The extracts are dried for 1 hour with sodium hydroxide and transferred to a dry Wurtz flask. The solvent is distilled off in a water bath, traces of the solvent are distilled off in an air bath (up to 100-110°C). Aniline is distilled with an air cooler at 180-182°C. Yield 2 - 2.3 g (70 - 75% of theoretical). p-Tolylhydrazine hydrochloride NH2 + N NaNO 2 - + NH NH3 Cl SnCl 2 - NH NH2. HCl 1. NaOH HCl HCl H3 C N Cl 2. HCl H3C H3 C 97 H3 C Reagents: p-toluidine - 16.1 g (0.15 mol); concentrated hydrochloric acid – 172 ml; sodium nitrite – 10.3 g (0.15 mol); tin chloride – 62 g (0.32 mol); 40% NaOH solution; methylene chloride; magnesium sulfate. P-toluidine and 110 ml of concentrated hydrochloric acid are placed in a 500 ml beaker equipped with a stirrer and thermometer. The resulting solution, while stirring, is cooled in an ice bath to 5°C and, maintaining this temperature, a solution of 10.3 g of NaNO2 in 30 ml of water is added to it from a dropping funnel. At the end of diazotization, the solution is filtered through a folded filter into a flask cooled with ice water and, with vigorous stirring, poured into a glass containing a solution of 62 g of SnCl2 cooled to 5°C in 62 ml of concentrated HC1. The precipitate that forms is filtered off on a Buchner funnel and squeezed well. Then it is suspended in 250 ml of water and, while cooling, alkalized with a 40% NaOH solution to a strongly alkaline reaction (pH  10 according to universal indicator paper). The temperature when adding alkali should not exceed 10°C. The reaction mass is extracted three times with methylene chloride in 100 ml portions, the extracts are dried over calcined MgSO4 (left overnight). Then a current of dry hydrogen chloride is passed into a solution of p-tolylhydrazine in methylene chloride. The precipitate that forms is filtered off, washed with ether and dried in a vacuum desiccator. Yield 14.7 g (62% of theoretical); Tpl. 205 - 206 °C. N-Benzyl-m-nitroaniline 98 O H H NO 2 N NO 2 NH NO 2 H2 C NaBH 4 + - H2 O MeOH H2 N Reagents: benzaldehyde – 2.5 g (0.023 mol); m-nitroaniline – 2.8 g (0.02 mol); benzene – 25 ml; methyl alcohol; sodium borohydride – 0.75 g (0.02 mol). 1. Synthesis of N-benzylidene-m-nitroaniline. Benzaldehyde, m-nitroaniline, 25 ml of benzene and several boiling pots are placed in a Wurtz flask with a capacity of 50 ml, the refrigerator is connected to the mixture and heated on an electric stove with a closed spiral until boiling. Using a graduated cylinder as a receiver, 22-24 ml of benzene is distilled off (this usually takes 25-30 minutes). The residue crystallizes after cooling. It is then recrystallized from a minimal amount of methyl alcohol. Yield 2.3 g (45% of theoretical); Tpl. 70 °C. 2. Reduction of N-benzylidene-m-nitroaniline. The resulting N-benzylidene-m-nitroaniline is placed in a three-neck flask with a capacity of 50-100 ml, equipped with a stirrer, a reflux condenser and a dropping funnel, and 20 ml of methyl alcohol is added there. To the resulting mixture, cooled to -30°C, add a solution of 0.75 g of NaBH4 in 15 ml of methyl alcohol, cooled to -30°C, with stirring for 3 minutes (see Note). Then the reaction mixture is refluxed for 15 minutes and, after cooling to room temperature, poured into 50 ml of water with stirring. After standing for 15 minutes and periodically stirring, the precipitated crystals 99 are filtered on a Buchner funnel, washed on a filter with water and dried on filter paper. Yield 2.1 g (90% of theoretical). If necessary, the product is recrystallized from ethyl alcohol; Melt 106-107 °C. Note: The borohydride solution is prepared at -30°C in no more than 5 minutes. before use, since sodium borohydride reacts with methyl alcohol; the flask with the solution cannot be tightly sealed (hydrogen is released): NaВН4 + 4СН3ОН → 4Н2 + СН3ОNa + B(OCH3)3 p-Chloroaniline. Reduction of 4-nitrochlorobenzene NO 2 NH2 H2 N NH2 Ni Cl Cl Reagents: 4-nitrochlorobenzene - 6.3 g (0.04 mol); hydrazine hydrate - 4-6 g (0.08 – 0.12 mol); skeletal nickel – 1 g; ethanol (rectified) – 140 ml. Carefully! Hydrazine is a strong poison. Work should only be carried out in a well-functioning fume hood. In a 250 ml round-bottomed flask equipped with a mechanical stirrer and a refrigerator, prepare a solution of 6.3 g (0.04 mol) of 4-nitrochlorobenzene in 140 ml of ethanol. A 23-fold molar excess of hydrazine hydrate is added to the solution, the contents of the flask are slightly heated in a water bath to 30-40°C and a suspension of skeletal nickel in alcohol is added in small 100 portions. In this case, foaming of the solution is observed. As the reaction proceeds (time can vary from 5 to 60 minutes), the yellow reaction mixture becomes almost colorless. Each subsequent portion of the catalyst is added after the release of gas (nitrogen) decreases. Completion of the reaction can be monitored by TLC. Eluent is chloroform. After the process is completed, a little more catalyst is added to the reaction flask, and the solution is heated at reflux to boiling to remove dissolved gaseous reaction products. The hot solution is filtered to remove nickel (see Note), boiled with activated carbon and filtered again. The cooled filtrate is poured into a large excess of water (~800 ml), the precipitate is filtered off and recrystallized from ethanol. Yield 4.1 g (80% of theoretical). Melting point: 71°C. Note: Dry catalyst is pyrophoric and spontaneously ignites in air. Therefore, filters with skeletal nickel should not be thrown into the wastepaper basket! All remnants of the used catalyst, including those on the filter, should be temporarily removed. complete destruction store under a layer of water. Reduction of 1-methylcyclopentene 3 NaBH 4 + o 0 - 10 C 4 BF 3. OEt 2 + 3 NaBF 4 + CH3 CH3 6 2 B 2 H6 + B 2H 6 2 101 CH3 CH3COOH 3B 4 Et 2O 6 Reagents: 1–methylcyclopentene - 32.6 g (0.4 mol); sodium borohydride – 3.8 g (0.1 mol); boron trifluoride etherate – 14.6 g (0.13 mol); diglyme (diethylene glycol dimethyl ether) – 15 ml; THF – 50 ml; acetic acid – 30 ml. Diborane, prepared from 3.8 g of sodium borohydride and 14.6 g of boron trifluoride etherate in diglyme, is transferred with a nitrogen stream into a solution of 32.6 g of 1-methylcyclopentene in 50 ml of tetrahydrofuran, maintaining the temperature at 0°C. The reaction mixture is stirred for 1 hour and then 30 ml of acetic acid is slowly added. The product is isolated by distillation, boiling point. 71.8oC. Yield 26 g (80% of theoretical). 11. SAFETY MEASURES Careless and careless work, failure to comply with safety precautions can lead to explosions, fires and accidents. Features of working with hydrogen Hydrogen is a flammable and explosive gas. It arrives at laboratories in cylinders painted green. 1. It is recommended to install the cylinder outside the building and in special metal cabinets. With this installation, gas is supplied to workplaces through copper or steel pipes. 2. Work with hydrogen must be carried out under draft, since a mixture of hydrogen and air is explosive. The permissible amount of hydrogen in laboratory premises should not exceed 5 liters (at a pressure of 150 atm). 3. The main danger associated with the use of hydrogen is the formation of explosive hydrogen-air mixtures, 102 the explosion limits of which in terms of the volume fraction of hydrogen are very wide: 3.3 – 81.5%. Greatest danger represents a mixture formed by two volumes of hydrogen and 4.8 volumes of air. Given this, special care should be taken when working with hydrogen. 4. Gas leaks must be avoided by carefully checking the tightness of all connections working installation. The presence of open flames and heated objects nearby should also be excluded. 5. You should start working with hydrogen after reading the safety instructions for working with gas cylinders and hydrogen. Special precautions when working with catalysts When dry in air, skeletal catalysts are pyrophoric, become very hot and can ignite surrounding objects. Given this property, they should be stored under a layer of liquid (water, alcohol, liquid hydrocarbons, etc.) and introduced in a wet state when loading into a reaction vessel. Skeleton catalysts prepared by the methods described above are especially active in hydrogenation processes at low pressures and temperatures not exceeding 100°C. At higher temperatures and pressures, the amount of catalyst should not exceed 5% of the amount of hydrogen acceptor. Failure to comply with these conditions can sometimes lead to a very violent reaction and a sharp increase in pressure. Skeletal nickel should not be used in dioxane solution at temperatures above 175°C, since in this case the reaction may be accompanied by an explosion. Residues of the catalyst should not be thrown into the trash bin, since, for example, Raney nickel is highly flammable. 103 Features of working with complex metal hydrides When working with complex metal hydrides, the following precautions must be taken. 1. You can work with complex metal hydrides only in protective glasses and gloves; you should carefully protect your respiratory organs from getting solutions and dust into them. Solutions of complex hydrides upon contact with the skin cause burns and lead to dermatitis if the exposed skin areas are not promptly washed with a dilute solution of acetic acid. Work only under traction! There should be no fire or hot objects nearby (for example, electric stoves). 2. In air at room temperature, complex metal hydrides are quite stable. Lithium aluminum hydride, probably due to the reaction of its surface layer with moisture and carbon dioxide in the air, forms a surface protective film aluminum hydroxide, which prevents its decomposition. However, upon prolonged storage it turns into a gray powder, very flammable and capable of exploding. This drug is not recommended for use and must be destroyed. 3. Complex metal hydrides must be carefully protected from moisture. Only sodium borohydride and sodium cyanoborohydride react slowly with water. In contrast, lithium aluminum hydride and many other hydrides can ignite and explode when in contact with even small amounts of water. The reaction of lithium aluminum hydride with water can be accompanied by an explosion and proceeds according to the following scheme: LiAlH4 + 4 H2O → 4 H2 + LiAl(OH)4 To store lithium aluminum hydride, it is better to use glass containers that are closed with rubber stoppers or tightly screwed caps. The vessels must first be filled with nitrogen. 4. Lithium aluminum hydride can also ignite when poured into glass funnels and crushed. For grinding, it is advisable to use hard rubber mortars and pestles wrapped in aluminum foil. Copper funnels should be used for pouring. 5. Spilled reaction mixtures may ignite in air after part of the solvent has evaporated, so they must be carefully covered with sand. 6. When working with complex metal hydrides, only freshly distilled, peroxide-free solvents should be used. Particularly dangerous in this sense are tetrahydrofuran and dialkyl ethers, of which diglyme is often used. The reaction between peroxides and aluminum hydrides is poorly controlled and explosions are possible. 7. When working with lithium aluminum hydride, remember that at temperatures above 100°C it decomposes, releasing hydrogen, which can be dangerous. Lithium aluminum hydride also reacts with OH-, SH-, NH- and CH-acids: LiAlH4 + 4 ROH → 4 H2 LiAlH4 + 4 R2NH → 4 H2 LiAlH4 + 4 RC≡CH → 4 H2 + LiAl(OR)4 + LiNR2 + Al(NR2)3 + LiC≡CR + Al(C≡CR)3 8. When working with complex metal hydrides, it is necessary to ensure that the hydrogen released during their decomposition is removed from a nearby flame, electric motors that can give a spark, etc. 9. The remains of complex metal hydrides to be destroyed are mixed in small portions with dry ether that does not contain peroxides, transferred to a flask with a stirrer and a reflux condenser, and a solution of dry ethyl acetate in ether is added dropwise until the boiling of the ether stops. 10. To extinguish the ignited hydride, it is recommended to cover the fires with sand, crushed chalk or table salt. The use of water, foam and carbon dioxide fire extinguishers is prohibited. Features of working with sodium metal 1. Sodium metal and its trimmings must be stored under a layer of kerosene. It should be removed from the kerosene in small portions, cut off under a layer of kerosene. The tweezers must be dry! 2. Kerosene is removed from the surface of the metal pieces with filter paper, on which the piece is cut into chips with a scalpel, transferring each chip with tweezers into the reaction flask. Waste metal sodium and filter paper on which sodium was cut are strictly prohibited from being thrown into the sewer, in a trash bin, etc. they should be destroyed by completely dissolving all traces of sodium in ethyl alcohol. After this, the paper is washed with water and discarded, the alcohol solution is poured into a waste bottle. 3. Contact of sodium with water or chlorine-containing compounds not intended for work should not be allowed. Water baths must not be used. A protective paper sleeve (made of filter paper) should be put on the refrigerator. You should work with oil, glycerin or sand baths. 4. In case of fires caused by working with alkali metals, do not use water, foam fire extinguishers or carbon dioxide. It is necessary to use dry sand, asbestos blankets, shovels, scoops. 106 12. QUESTIONS FOR SELF-CHECK 1. What reactions in organic chemistry are called reduction? 2. What reducing agents are used in laboratory practice? 3. Name reducing agents based on boron and aluminum hydrides. 4. Write the reactions for the preparation of complex alkoxyaluminum hydrides. 5. What hydride equivalent (according to theory) should be used when reducing nitriles to primary amines; to aldehydes? 6. What heterogeneous hydrogenation catalysts do you know? 7. What is the advantage of homogeneous hydrogenation compared to heterogeneous? 8. Give examples of hydrogenolysis reactions and give a definition. 9. How does the structure of an alkene affect the rate of hydrogenation? 10. Give an example of a hydroboration reaction. 11. What catalyst is used for the hydrogenation of alkynes to cisalkenes? 12. What reducing agent should be used to obtain transbutene-2 ​​from butine-2? 13. Why in the Cannizzaro cross reaction from a mixture of two aldehydes does formaldehyde undergo oxidation, while the other aldehyde is reduced to alcohol? 14. What reducing agent must be used, and under what conditions, in order to obtain an aromatic amine from an aromatic nitro compound? 15. What reagent must be used, and under what conditions, to obtain hydrazobenzene from nitrobenzene? 16. In what cases is the reduction of aldehydes or ketones carried out according to Clemmensen, and in which according to Kizhner-Wolff? 17. Write the reaction for the reduction of diazonium salt with sodium sulfite. 18. Why must glassware and reagents be thoroughly dried when working with lithium aluminum hydride? 19. Write the reaction products and name them: a) O O C H CH2 C 107 O CH3 LiAlH4 b) O CH3 N LiAlH4 CH3 c) CH3 O Li NH3 d) O OH Li NH3 e) C N LiAlH 4 20. Complete the following reactions: a) O H2/Pt EtOH b) O (CH3)3C C NaBH4 CH2Br i-PrOH c) O CH3(CH2)6C H Na EtOH d) OH H2 OH 108 Kt 21. Write the product that is predominantly formed from m-nitrotoluene in each from the following reactions: a) Zn, NaOH – EtOH; b) Fe, NH4Cl (aq); c) Zn, NaOH (aq); d) H2/Pt; e) SnCl2, HCl Bibliography 1. Workshop on organic chemistry / Ed. Academician of the Russian Academy of Sciences N.S. Zefirova. - M.: BINOM. Knowledge Laboratory, 2010. – 568 p. 2. Borovlev I.V. Organic chemistry: terms and basic reactions. - M.: BINOM. Knowledge Laboratory, 2010. – 359 p. 3. Dyadchenko V.P., Trushkov I.V., Brusova G.P. Synthetic methods of organic chemistry: Textbook. manual, Part 1-2. – M.: Khimmed, 2004. – 154 p. 4. Organic chemistry: Textbook. manual, Part 4. – M.: Publishing house of the chemical faculty of Moscow State University. M.V. Lomonosov, 2002. – 143 p. 5. Organic chemistry: Textbook. manual, Part 1. – M.: Publishing house of the chemical faculty of Moscow State University. M.V. Lomonosova, 2002. – 102 p. 6. Repinskaya I.B., Shvartsberg M.S. Selected methods for the synthesis of organic compounds: Textbook. allowance – Novosibirsk: Novosibirsk Publishing House. Univ., 2000. – 284 p. 7. Carey F., Sandberg R. Advanced course in organic chemistry. – M.: Chemistry, 1981. – 254 p. 8. Lebedev N.N. Chemistry and technology of basic organic and petrochemical synthesis. – M.: Chemistry, 1988. – 592 p. 109 9. Passet B.V. Basic processes of chemical synthesis of biologically active substances. – M.: GEOTAR-MED, 2002. – 376 p. 10. Organikum: Workshop on organic chemistry: In 2 volumes / Transl. with him. – M.: Mir, 1979. – T.2. 442 pp. 11. Modern methods of organic synthesis / Ed. B.V. Ioffe. – L.: Publishing house Leningr. University, 1980. – 232 p. 12. Terney A. Modern organic chemistry: In 2 volumes - M.: Mir, 1981. 13. Hayosh A. Complex hydrides in organic chemistry. – L.: Chemistry, 1971. – 624 p. 14. Fizer L., Fizer M. Reagents for organic synthesis. In 6 volumes - M.: Mir, 1970-1975. 110 APPENDICES Appendix 1 Reactivity of various functional groups in reactions with complex metal hydrides at temperatures 0 – 25 ° C Reaction RCHO  RCH2OH R2CO  R2CHOH RCOCl  RCH2OH Lactone  diol Epoxide  alcohol R1COOR2  R1CH2OH + R2OH RCOOH  RCH2OH RCOO -  RCH2OH RCONR2  RCHNR2 RCN → RCH2NH2 RNO2  RNH2 RHAL  RH RH = CH2  RCH2CH3 LIALH4 NABH4 LIBH4 Lialh (OME) 3 Lialh2 (Och2ch2ome) 2 Libhet3 NabH3CN DIGLIM + + + + + + + LIALH (Too Bu) 3 TGF + + + - ether + + + + + + methanol + + + - THF + + + + + + + + + + + + ether + + + + + - + + - + + + + - - - + + + + + + + + + + + - + + - - - - + + - + - + + - + - Note. A plus indicates the presence of a reaction, a minus indicates a very slow reaction. 109 Appendix 2 Solubility of some complex metal hydrides at a temperature of 255оС (g per 100 g of solvent) Hydride Solvent H2O MeOH EtOH Et2O ТHF Dioxane Glim Diglyme LiAlH4 LiBH4 NaBH4 NaBH3CN 55 212 13 28 0.1 37.2 0.1 0.06 - 7 0.8 - 5 5.5 17.6 - 2.5 20 Slightly soluble - 35 – 40 2.5 0 0 NaBH(OMe)3 2.5 16.4 Very soluble - - - 1.64 - - LiAlH(O-tBu)3 - - - 2 36 - 4 41 110 111

Samara State Technical University Department of Organic Chemistry REPORT on the internship Place of internship: LLC PKF "Vershina" Head of practice from the enterprise: Kondratyev V. A. Student III-xt-6 Anashkin Yuri

Goal: Consolidation of theoretical and practical knowledge obtained in the study of general professional disciplines; Objectives: Familiarization with the organization of work at industrial enterprises Mastering the specialty of a spectral analysis laboratory assistant Studying regulatory and informational literature and documentation (GOST, TU, etc.) Obtaining modern ideas about the integrated use of raw materials and waste recycling

Products - Production of aluminum alloys according to the requirements of GOST 1583-93 or according to the Customer's specifications, including - Castings of various complexity groups weighing up to 20 kg. - Forgings of various complexity groups, produced in open dies on hot stamping presses

PKF Vershina LLC produces and sells aluminum alloys of the AK 12, AK 9 h, AK 7 h, AK 5 M 2, AK 9 M 2, AK 12 MMg grades. N, AK 12 M 2 Mg. N and many other brands.

Laboratory The spectral laboratory of Vershina PKF LLC is equipped with a modernized complex for carrying out spectral analysis of metals and alloys, corresponding to the DFS-500 spectrophotometer. The time for chemical analysis is 5÷ 15 minutes. Process stability and analysis accuracy are ensured by the use of argon in the installation high frequency, and high-quality GSO samples.

Atomic emission spectroscopy The operating principle of an optical emission spectrometer is based on the fact that the atoms of each element can emit light of certain wavelengths - spectral lines. In order for atoms to start emitting light, they must be excited - by heat, electrical discharge, laser or some other means. The more atoms of a given element are present in the analyzed sample (sample), the brighter the radiation of the corresponding wavelength will be.

After the reorganization of the medical institute into the Military Medical Academy (July 1939-1942), the head of the department was associate professor Vladimir Alekseevich Solomin, who headed the department until November 1962. He published the textbook “General and Inorganic Chemistry,” which was characterized by its original presentation of chemistry issues and was popular. From 1963 to 1983, the department was headed by Associate Professor Viktor Ivanovich Batalin, who provided translation educational process departments to the modern level both in educational and methodological and scientific terms, laid the foundations for specialized teaching of chemistry in the newly opened faculties - pediatrics, dentistry and pharmaceuticals.

Head of the Department of General, Bioinorganic and Bioorganic Chemistry, Professor N. P. Avvakumova

In accordance with the new curriculum, from September 1, 1982, the department received a new name - the Department of Bioinorganic and Biophysical Chemistry. From September 1, 1983 to September 1, 2008, the department was headed by Albert Ivanovich Agapov, a graduate of Leningrad State University, who was also the organizer and first dean of the Faculty of Pharmacy of SamSMU, now an honorary professor of SamSMU. In the 1985-86 academic year, the course of organic chemistry, previously taught at the Department of Biochemistry, was transferred to the department and the department became known as the Department of General, Bioinorganic and Bioorganic Chemistry.

Since September 2008, the department has been headed by a graduate of the first graduating class of the Faculty of Pharmacy, an honorary graduate of the university, Doctor of Biological Sciences, Professor Nadezhda Petrovna Avvakumova. During her student years, for 5 years she headed the Komsomol organization of the Faculty of Pharmacy, and in 1975 she was photographed near the Victory Banner.

Highly qualified teaching and laboratory staff are involved in teaching: 2 professors, 4 associate professors, 4 senior teachers; sedateness 100%, average age employees 52 years old.

Educational work of the department

Educational work is aimed at implementing a model of student-oriented and advanced education of specialists, contributes to obtaining professional knowledge, personality development. Chemistry teaching is carried out at a high scientific and pedagogical level using both traditional and modern methods of teaching and monitoring students' knowledge.

The department provides training for students of various faculties of full-time, part-time and part-time forms of study. The following disciplines of the basic curricula are assigned to the department of general, bioinorganic and bioorganic chemistry:

• Specialty "General Medicine": chemistry;
• Specialty "Pediatrics": chemistry;
• Specialty “Medical and preventive care”: general and bioorganic chemistry;
• Specialty "Dentistry": chemistry;
• Specialty "Pharmacy": general and inorganic chemistry;

The educational process is carried out in accordance with the goals and skills established by the State Educational Standards of each specialty and areas of training. The goals and acquired skills in specific disciplines assigned to the department are set out in work programs, educational and thematic plans for the relevant disciplines and comply with the requirements of the State Standards.

A special feature of teaching the discipline at the department is its medical and biological focus. The curriculum includes selected sections of general, bioinorganic, bioorganic, physical, colloidal and analytical chemistry, which, organically combined, essentially form the course “Chemical foundations of the vital processes of the body”, necessary for the formation of natural-scientific thinking of medical specialists. This course lays the foundation for understanding the principles of evidence-based medicine. Each section (module) of this course equips medical students with the knowledge they need to understand and master the essence and mechanism of processes occurring in the body at the molecular level.

The staff of the Department of General, Bioinorganic and Bioorganic Chemistry

The lecture course is delivered using multimedia projectors; All chemical laboratories are equipped with the necessary equipment and reagents.

A lot of work is carried out by the staff of the department within the framework of the faculty of pre-university preparation: they provide advisory assistance to chemistry teachers in medical classes, participate in the Olympiad movement of schoolchildren “The Future of Medicine”, and provide teaching within the framework of preparatory courses at SamSMU.

Scientific work of the department

Currently, it has been possible to form a unified scientific direction of the department “Study of the structure, properties and biological activity of specific organic substances of medicinal mud and preparations based on them,” which is currently relevant, patentable and innovative. In this area, two doctoral dissertations were completed (A. I. Agapov, 1999 and Avvakumova N. P., 2003) and 8 candidate dissertations, 13 patents and 4 grants were received, 2 of which were international.

As part of the scientific congress in Tomsk in 2010, the department was recognized as the leading center in the Russian Federation for the study of the biological activity of humic substances.

Professor A. I. Agapov was awarded the highest award of the AMTS of the Russian Federation for the development of the theory and practice of using humic preparations - the A. Chizhevsky Gold Medal.

The department, within the framework of creative cooperation, implements its projects together with many universities in the country: Moscow State University, Samara State University, BSU, BSMU (Ufa), Kemerovo State Medical Academy (Kemerovo). The department conducts experimental research with scientific centers: Research Institute “Institute of Experimental Medicine and Biotechnology” (Samara); "Institute of Petrochemistry and Catalysis RAS" (Ufa), NPO "Khimavtomatika" (Moscow).

Throughout the existence of the department, its employees have been actively interacting with students within the framework of the student scientific society. Students, together with teachers, successfully carry out scientific and experimental work, the results of which are numerous diplomas, grants and certificates.

Activists of the student scientific circle and young scientists of the department speak at various international, all-Russian and regional conferences.

Educational work

The Department of General, Bioinorganic and Bioorganic Chemistry supervises students of the pediatric and pharmaceutical faculties. Teachers supervise educational, research, cultural and educational work, and participate in the organization of various exhibitions and concerts. Joint visits to theaters are carried out, and discussions are held on current topical issues. The most striking events of student life are reflected in the wall newspaper “Our Curated Sponsored Flow.” Based on the results of the winter session, which is the first in the student life of first-year students, letters of thanks are sent to the parents of students who received an “excellent” grade. The events carried out contribute to the general cultural and moral education of students.