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III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] Alcohol oxidation Alcohol oxidation is an important organic reaction. Primary alcohols (R-CH2-OH) can be oxidized either to aldehydes (R-CHO) or to carboxylic acids (R-CO2H), while the oxidation of secondary alcohols (R1R2CH-OH) normally terminates at the ketone (R1R2C=O) stage. Tertiary alcohols (R1R2R3C-OH) are resistant to oxidation. The direct oxidation of primary alcohols to carboxylic acids normally proceeds via the corresponding aldehyde, which is transformed via an aldehyde hydrate (R-CH(OH)2) by reaction with water before it can be further oxidized to the carboxylic acid. Often it is possible to interrupt the oxidation of a primary alcohol at the aldehyde level by performing the reaction in absence of water, so that no aldehyde hydrate can be formed. 1. Oxidation to aldehydes Reagents useful for the transformation of primary alcohols to aldehydes are normally also suitable for the oxidation of secondary alcohols to ketones. These include: Chromium-based reagents, such as Collins reagent (CrO3·Py2), PDC (Pyridinium dichromate) or PCC(Pyriinium chlorochromate). Activated DMSO, resulting from reaction of DMSO with electrophiles, such as oxalyl chloride (Swern oxidation). Hypervalent iodine compounds, such as Dess-Martin periodinane or 2-Iodoxybenzoic acid. Allylic and benzylic alcohols can be oxidized in presence of other alcohols using certain selective oxidants such as manganese dioxide (MnO2). 2. Oxidation to ketones 1 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] Reagents useful for the oxidation of secondary alcohols to ketones, but normally inefficient for oxidation of primary alcohols to aldehydes, include chromium trioxide (CrO3) in a mixture of sulfuric acid and acetone (Jones oxidation) and certain ketones, such as cyclohexanone, in the presence of aluminium isopropoxide (Oppenauer oxidation). Another method is oxoammonium-catalyzed oxidation. 3. Oxidation to carboxylic acids The direct oxidation of primary alcohols to carboxylic acids can be carried out using: Potassium permanganate (KMnO4). Jones oxidation. (The Jones oxidation, is an organic reaction for the oxidation of primary and secondary alcohols to carboxylic acids and ketones, respectively) PDC in DMF. Heyns oxidation. Ruthenium tetroxide (RuO4). TEMPO. (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl or TEMPO is a chemical compound with the formula (CH2)3(CMe2)2NO. 4. Diol oxidation Alcohols possessing two hydroxy groups located on adjacent carbons —that is, 1,2-diols— suffer oxidative breakage at a carbon-carbon bond with some oxidants such as sodium periodate (NaIO4) or lead tetraacetate (Pb(OAc)4), resulting in generation of two carbonyl groups. The reaction is also known as glycol cleavage. Sharpless epoxidation The Sharpless epoxidation reaction is an enantioselective chemical reaction to prepare 2,3epoxyalcohols from primary and secondary allylic alcohols. The stereochemistry of the resulting epoxide is determined by the diastereomer of the chiral tartrate diester (usually diethyl tartrate or diisopropyl tartrate) employed in the reaction. The 2 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] oxidizing agent is tert-butyl hydroperoxide. Enantioselectivity is achieved by a catalyst formed from titanium tetra(isopropoxide) and diethyl tartrate. The Sharpless epoxidation's success is due to five major reasons. First, epoxides can be easily converted into diols, aminoalcohols or ethers, so formation of chiral epoxides is a very important step in the synthesis of natural products. Second, the Sharpless epoxidation reacts with many primary and secondary allylic alcohols. Third, the products of the Sharpless epoxidation frequently have enantiomeric excesses above 90%. Fourth, the products of the Sharpless epoxidation are predictable using the Sharpless Epoxidation model. Finally, the reactants for the Sharpless epoxidation are commercially available and relatively cheap. Synthetic utility The Sharpless epoxidation is viable with a large range of primary and secondary olefinic alcohols. To demonstrate the synthetic utility of the Sharpless Epoxidation, the Sharpless group created synthetic intermediates of various natural products: methymycin, erythromycin, leukotriene C-1, and (+)-disparlure. The Sharpless epoxidation has been used for the total synthesis of various carbohydrates, terpenes, leukotrienes, pheromones, and antibiotics. The main drawback of this protocol is the necessity of the presence of an allylic alcohol. The Jacobsen epoxidation, an alternative method to enantioselectively oxidise alkenes, overcomes this issue and tolerates a wider array of functional groups. Jacobsen epoxidation The Jacobsen Epoxidation, sometimes also referred to as Jacobsen-Katsuki Epoxidation is a chemical reaction which allows enantioselective epoxidation of unfunctionalized alkyl- and aryl- substituted olefins. It is complementary to the Sharpless epoxidation (used to form epoxides from the double bond in allylic alcohols). 3 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] The Jacobsen epoxidation gains its stereoselectivity from a C2 symmetric manganese(III) salen-like ligand, which is used in catalytic amounts. The manganese atom transfers an oxygen atom from chlorine bleach or similar oxidant. Jacobsen's catalysts R = Alkyl, O-alkyl, O-trialkyl Best Jacobsen Catalyst: R = tBu Katsuki's Catalysts R1 = Aryl, substituted aryl R2 = Aryl, Alkyl The reaction is named after its inventor, Eric Jacobsen, and sometimes also including Tsutomu Katsuki. Chiral-directing catalysts are useful to organic chemists trying to control the stereochemistry of biologically active compounds and develop enantiopure drugs. A general reaction scheme follows: Mechanism 4 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] The mechanism of the Jacobsen–Katsuki epoxidation is not fully understood, but most likely a manganese(V)-species is the reactive intermediate which is formed upon the oxidation of the Mn(III)-salen complex. The most accepted mechanism is the concerted pathway mechanism. After the formation of the Mn(V) complex, the catalyst is activated and therefore can form epoxides with alkenes. The alkene comes in from the "top-on" approach (above the plane of the catayst) and the oxygen atom now is bonded to the two carbon atoms (previously C=C bond) and is still bonded to the manganese metal. Then, the Mn–O bond breaks and the epoxide is formed. The Mn(III)-salen complex is regenerated, which can then be oxidized again to form the Mn(V) complex. The Jacobsen Epoxidation allows the enantioselective formation of epoxides from various cis-substituted olefins by using a chiral Mn-salen catalyst and a stoichiometric oxidant such as bleach. Compared to the Sharpless Epoxidation, the Jacobsen Epoxidation allows a broader substrate scope for the transformation: good substrates are conjugated cisolefins (R: Ar, alkenyl, alkynyl; R': Me, alkyl) or alkyl-substituted cis-olefins bearing one bulky alkyl group. Shi Epoxidation The Shi Epoxidation allows the synthesis of epoxides from various alkenes using a fructose-derived organocatalyst with Oxone as the primary oxidant. It is notable as not requiring metal catalysts. The mechanism involves the formation of a dioxirane intermediate. 5 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] or Mechanism The epoxidizing species is believed to be a dioxirane, which is a powerful epoxidation reagent. These are not indefinitely stable, but can be generated in situ by oxidation of a ketone with potassium peroxymonosulfate (Oxone). The sulfate - as a good leaving group facilitates the ring closure to the dioxiranes. As the ketone is regenerated, only catalytic amounts of it are needed. In addition, chiral ketones can be used for a catalyzed, enantioselective epoxidation, since the ketone substituents are close to the reacting center. Reactions are conducted in buffered, often biphasic mixtures with phase transfers catalysts. Addition of K2CO3 to the reaction mixture increases the rate of formation of the dioxirane but also lowers the stability of Oxone. However, a higher pH also disfavors the Bayer-Villiger Oxidation as a side reaction, so the catalysts remain more active. Therefore 6 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] the autodecomposition of Oxone at high pH can be overridden if the ketone is sufficiently reactive. The enhancements in reaction rate can also be explained by a higher nucleophility of Oxone under more basic conditions. In any case, a careful use of buffered media is often needed. This procedure generates epoxides with high enantiomeric excesses from transdisubstituted alkenes and trisubstituted alkenes. Cis-disubstituted alkenes and styrenes are asymmetrically epoxidized using a similar catalyst. Prévost Reaction and Woodward modification The Prévost Reaction allows the synthesis of anti-diols from alkenes by the addition of iodine followed by nucleophilic displacement with benzoate in the absence of water. Hydrolysis of the intermediate diester gives the desired diol. That is, It is chemical reaction in which an alkene is converted by iodine and the silver salt of benzoic acid to a vicinal diol with anti stereochemistry. The reaction was discovered by the French chemist Charles Prévost (1899-1983). The Woodward Modification of the Prévost Reaction gives syn-diols. Mechanism The initial addition of iodine leads to a cyclic iodonium ion, which is opened through nucleophilic substitution by benzoate anion: A neighbouring-group participation mechanism prevents the immediate nucleophilic substitution of iodine by a second equivalent of benzoate that would lead to a syn-substituted product. Instead, a cyclic benzoxonium ion intermediate is formed: 7 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] Opening of this intermediate by a second addition of benzoate gives the anti-substituted dibenzoate: Hydrolysis then delivers the diol. In the Woodward-Modification, added water decomposes the above benzoxonium intermediate directly to a syn-substituted diol. Drawbacks The use of expensive silver salts, the requirement for a stoichiometric amount of molecular halogen, and the formation of a relatively large amount of organic and inorganic wastes are definite drawbacks to this reaction. Woodward cis-Hydroxylation The Woodward Reaction allows the synthesis of syn-diols from alkenes by the addition of iodine followed by nucleophilic displacement with acetate in the presence of water. Hydrolysis of the intermediate ester gives the desired diol. The Prévost Reaction gives anti-diols. Hydroboration–oxidation reaction The hydroboration–oxidation reaction is a two-step organic reaction that converts an alkene into a neutral alcohol by the net addition of water across the double bond. The hydrogen and hydroxyl group are added in a syn addition leading to cis stereochemistry. It is a two step pathway used to produce alcohols. The reaction proceeds in an AntiMarkovnikov manner, where the hydrogen (from BH3 or BHR2) attaches to the more substituted carbon and the boron attaches to the least substituted carbon in the alkene bouble 8 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] bond. Furthermore, the borane acts as a lewis acid by accepting two electrons in its empty p orbital from an alkene that is electron rich. This process allows boron to have an electron octet. A very interesting characteristic of this process is that it does not require any activation by a catalyst. The Hydroboration mechanism has the elements of both hydrogenation and electrophilic addition and it is a stereospecific (syn addition), meaning that the hydroboration takes place on the same face of the double bond, this leads cis stereochemistry. The general form of the reaction is as follows: Tetrahydrofuran (THF) is the archetypal solvent used for hydroborations. Mechanism and scope In the first step, borane (BH3) adds to the double bond, transferring one hydrogen from itself to the adjacent carbon. This reaction, hydroboration is repeated two additional times so that three alkenes add to each BH3. The resulting trialkylborane is treated with hydrogen peroxide in the second step. This process replaces the B-C bonds with HO-C bonds. The boron reagent is converted to boric acid. The reaction was originally described by H.C. Brown in 1957 for the conversion of 1-hexene into 1-hexanol. Until all hydrogens attached to boron have been transferred away, the boron group BH2 will continue adding to more alkenes. This means that one mole of hydroborane will undergo the reaction with three moles of alkene. Furthermore, it is not necessary for the hydroborane to have more than one hydrogen. For example, reagents of the type R 2BH are commonly used, where R can represents the remainder of the molecule. Such modified hydroboration reagents include 9-BBN, catecholborane, and disiamylborane. Alkyne hydroboration 9 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] A hydroboration reaction also takes place on alkynes. Again the mode of action is syn and secondary reaction products are aldehydes from terminal alkynes and ketones from internal alkynes. In order to prevent hydroboration across both the pi-bonds, a bulky borane like disiamyl (di-sec-iso-amyl) borane is used. Baeyer-Villiger Oxidation The Baeyer-Villiger Oxidation is the oxidative cleavage of a carbon-carbon bond adjacent to a carbonyl, which converts ketones to esters and cyclic ketones to lactones. The Baeyer-Villiger can be carried out with peracids, such as MCBPA, or with hydrogen peroxide and a Lewis acid. The Baeyer–Villiger oxidation is an organic reaction in which a ketone is oxidized to an ester by treatment with peroxy acids or hydrogen peroxide. Key features of the Baeyer– Villiger oxidation are its stereospecificity and predictable regiochemistry. It is named after the German chemist Johann Friedrich Wilhelm Adolf von Baeyer (1835–1917) and the Swiss 10 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] chemist Victor Villiger (1868–1934). This reaction is also called Baeyer–Villiger rearrangement. Reagents typically used to carry out this rearrangement are meta-chloroperoxybenzoic acid (mCPBA), peroxyacetic acid, or peroxytrifluoroacetic acid. Reactive or strained ketones (cyclobutanones, norbornanones) react with hydrogen peroxide or hydroperoxides to form lactones. The original reagent in the 1899 publication is Caro's acid discovered just a year earlier. Disodium phosphate or sodium bicarbonate is often added as a buffering agent to prevent transesterification or hydrolysis. The regiospecificity of the reaction depends on the relative migratory ability of the substituents attached to the carbonyl. Substituents which are able to stabilize a positive charge migrate more readily, so that the order of preference is: tert. alkyl > cyclohexyl > sec. alkyl > phenyl > prim. alkyl > CH3. In some cases, stereoelectronic or ring strain factors also affect the regiochemical outcome. Mechanism The reaction mechanism of this oxidative cleavage involves first addition of the peroxy acid to the carbonyl forming a tetrahedral intermediate also called the Criegee intermediate for its similarity with rearrangement of that name. The transition state for this step is envisioned as a hydrogen relay involving three peroxy acid molecules with linear OH-O interactions. Next is a concerted migration of one of the adjacent carbons to oxygen with loss of a carboxylic acid. If the migrating carbon is chiral, the stereochemistry is retained. Migratory aptitude: hydrogen > tertiary alkyl > secondary alkyl > phenyl > primary alkyl > methyl In the transition state for this migration step the R–C–O–O dihedral angle should be 180 °C to maximise the interaction between the filled R–C sigma bond and the antibonding O–O sigma bond. This step is also (at least in silico) assisted by two or three peroxyacid units enabling the hydroxyl proton to shuttle to its new position. Wacker-Tsuji Oxidation 11 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] The Wacker Oxidation is an industrial process, which allows the synthesis of ethanal from ethene by palladium-catalyzed oxidation with oxygen. Copper serves as redox cocatalyst. The lab scale modification - the Wacker-Tsuji Oxidation - is useful for the synthesis of various ketones. Mechanism The mechanism is typical of palladium olefin chemistry, and water serves as the oxygen source; the reduced palladium is reoxidized by Cu(II) and ultimately by atmospheric oxygen. Ozonolysis Ozonolysis is the cleavage of an alkene or alkyne with ozone to form organic compounds in which the multiple carbon–carbon bond has been replaced by a double bond to oxygen. The outcome of the reaction depends on the type of multiple bond being oxidized and the workup conditions. Ozonolysis of alkenes Alkenes can be oxidized with ozone to form alcohols, aldehydes or ketones, or carboxylic acids. In a typical procedure, ozone is bubbled through a solution of the alkene in methanol at −78 °C until the solution takes on a characteristic blue color, which is due to unreacted ozone. This indicates complete consumption of the alkene. Alternatively, various other chemicals can be used as indicators of this endpoint by detecting the presence of ozone. If ozonolysis is performed by bubbling a stream of ozone-enriched oxygen through the reaction mixture, the gas that bubbles out can be directed through a potassium iodide solution. When the solution has stopped absorbing ozone, the ozone in the bubbles oxidizes the iodide to 12 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] iodine, which can easily be observed by its violet color. For closer control of the reaction itself, an indicator such as Sudan Red III can be added to the reaction mixture. Ozone reacts with this indicator more slowly than with the intended ozonolysis target. After completing the addition a reagent is then added to convert the intermediate ozonide to a carbonyl derivative. Reductive work-up conditions are far more commonly used than oxidative conditions. The use of triphenylphosphine, thiourea, zinc dust, or dimethyl sulfide produces aldehydes or ketones while the use of sodium borohydride produces alcohols. The use of hydrogen peroxide produces carboxylic acids. Recently, the use of amine N-oxides has been reported to produce aldehydes directly. Other functional groups, such as benzyl ethers, can also be oxidized by ozone. Dichloromethane is often used as a 1:1 cosolvent to facilitate timely cleavage of the ozonide. An example is the ozonolysis of eugenol converting the terminal alkene to an aldehyde: In the generally accepted mechanism proposed by Rudolf Criegee in 1953, the alkene and ozone form an intermediate molozonide in a 1,3-dipolar cycloaddition. Next, the molozonide reverts to its corresponding carbonyl oxide (also called the Criegee intermediate or Criegee zwitterion) and aldehyde or ketone in a retro-1,3-dipolar cycloaddition. The oxide and aldehyde or ketone react again in a 1,3-dipolar cycloaddition or produce a relatively stable ozonide intermediate (a trioxolane). 13 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] Ozonolysis of alkynes Ozonolysis of alkynes generally gives an acid anhydride or diketone product, not complete fragmentation as for alkenes. A reducing agent is not needed for these reactions. The exact mechanism is not completely known. If the reaction is performed in the presence of water, the anhydride hydrolyzes to give two carboxylic acids. Ozonolysis of elastomers The method was used to confirm the structural repeat unit in natural rubber as isoprene. It is also a serious problem, known as "ozone cracking" where traces of the gas in an atmosphere will attack and split double bonds in susceptible elastomers, including natural rubber, polybutadiene, Styrene-butadiene and Nitrile rubber. Ozone cracking creates small cracks at right angles to the load in the surfaces exposed to the gas, the cracks growing steadily as attack continues. The rubber product must be under tension for crack growth to occur. 14 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] Ozone cracking is a form of stress corrosion cracking where active chemical species attack products of a susceptible material. Ozone cracking is a serious problem in fuel lines since cracks can penetrate the bore and cause a fuel leak, leading to fires or spillage of diesel fuel onto roads for example. Spills are especially hazardous since the slick is extremely slippery and is the cause of many road accidents, especially those involving motorcyclists. Ozone cracking was once commonly seen in the sidewalls of tires but is now rare owing to the use of antiozonants. Other means of prevention include replacing susceptible rubbers with resistant elastomers such as polychloroprene, EPDM or fluoroelastomers such as Viton. Allylic Oxidation The functionalization of allylic positions can be done by several distinct methods (allylic halogenation, singlet oxygen, selenium dioxide). Chromium oxide reagents are one of the options to do this difficult transformation. In favorable cases, Cr(VI) complexes will oxidize alkenes to enones. Selenium dioxide Selenium dioxide is the colorless solid chemical compound with the formula SeO2. Properties Solid SeO2 is a one-dimensional polymer, the chain consisting of alternating selenium and oxygen atoms. Each Se atom is pyramidal and bears a terminal oxide group. The relative stereochemistry at Se alternates along the polymer chain (syndiotactic). In the gas phase selenium dioxide is present as dimers and other oligomeric species, at higher temperatures it is monomeric. Monomeric SeO2 is a polar molecule, with the dipole moment of 2.62 D pointed from the midpoint of the two oxygen atoms to the selenium atom. SeO2 is considered an acidic oxide: it dissolves in water to form selenous acid. Often the terms selenous acid and selenium dioxide are used interchangeably. It reacts with base to form selenite salts containing the SeO2−3 anion. For example, reaction with sodium hydroxide produces sodium selenite: 15 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] SeO2 + 2 NaOH → Na2SeO3 + H2O Preparation Selenium dioxide is prepared by oxidation of selenium by burning in air and nitric acid or by reaction with hydrogen peroxide, but perhaps the most convenient preparation is by the dehydration of selenous acid. 3 Se + 4 HNO3 + H2O → 3 H2SeO3 + 4 NO 2 H2O2 + Se → SeO2 + 2 H2O H2SeO3 ⇌ SeO2 + H2O Uses Organic synthesis SeO2 is an important reagent in organic synthesis. Oxidation of paraldehyde (acetaldehyde trimer) with SeO2 gives glyoxal and the oxidation of cyclohexanone gives cyclohexane-1,2-dione. The selenium starting material is reduced to selenium, and precipitates as a red amorphous solid which can easily be filtered off. As a colorant Selenium dioxide imparts a red colour to glass. It is used in small quantities to counteract the blue colour due to cobalt impurities and so to create (apparently) colourless glass. In larger quantities, it gives a deep ruby red colour. Selenium dioxide is the active ingredient in some cold-blueing solutions. It was also used as a toner in photographic developing. Ritter Reaction The Ritter reaction is a chemical reaction that transforms a nitrile into an N-alkyl amide using various electrophilic alkylating reagents. The original reaction formed the alkylating agent using an alkene in the presence of a strong acid. 16 III Semester M Sc-Organic synthesis via Oxidation and Reduction[Type the document title] Primary, secondary, tertiary, and benzylic alcohols, as well as tert-butyl acetate, also successfully react with nitriles in the presence of strong acids to form amides via the Ritter reaction. The Ritter reaction proceeds by the electrophilic addition of either the carbenium ion 2 or covalent species to the nitrile. The resulting nitrilium ion 3 is hydrolyzed by water to the desired amide 5. Applications The Ritter reaction is most useful in the formation of amides in which the nitrogen has a tertiary alkyl group. It is also used in industrial processes as it can be effectively scaled up from laboratory experiments to large-scale applications while maintaining high yield. Real world applications include Merck’s industrial-scale synthesis of anti-HIV drug Crixivan, the synthesis of the alkaloid aristotelone, and synthesis of Amantadine, an antiviral and antiparkinsonian drug. Other applications of the Ritter reaction include synthesis of dopamine receptor ligands and production of amphetamine from allylbenzene. A problem with the Ritter reaction is the necessity of an extremely strong acid catalyst in order to produce the carbocation. This corrosive type of chemical poses an environmental hazard for chemical waste and safety risk for running the reaction itself. 17