Oxidation

Oxidation

First, we must examine what we mean when we speak of oxidation and reduction.Inorganic chemists define oxidation in two ways: loss of electrons and increase inoxidation number. In organic chemistry, these definitions, while still technicallycorrect, are not easy to apply. While electrons are directly transferred in someorganic oxidations and reductions, the mechanisms of most of these reactions donot involve a direct electron transfer. As for oxidation number, while this is easyto apply in some cases, (e.g., the oxidation number of carbon in CH4 is -4), inmost cases attempts to apply the concept lead to fractional values or to apparentabsurdities. Thus carbon in propane has an oxidation number of -2.67 and inbutane of -2.5, although organic chemists seldom think of these two compoundsas being in different oxidation states. An improvement could be made by assigningdifferent oxidation states to different carbon atoms in a molecule, depending onwhat is bonded to them (e.g., the two carbons in acetic acid are obviously in differentoxidation states), but for this a whole set of arbitrary assumptions would berequired, since the oxidation number of an atom in a molecule is assigned onthe basis of the oxidation numbers of the atoms attached to it. There would seem littleto be gained by such a procedure. The practice in organic chemistry has been to setup a series of functional groups, in a qualitative way, arranged in order of increasingoxidation state, and then to define oxidation as the conversion of a functional groupin a molecule from one category to a higher one. Reduction is the opposite. For thesimple functional groups this series is shown in Table below. Note that this classificationapplies only to a single carbon atom or to two adjacent carbon atoms. Thus1,3-dichloropropane is in the same oxidation state as chloromethane, but1,2-dichloropropane is in a higher one. Obviously, such distinctions are somewhat

arbitrary, and if we attempt to carry them too far, we will find ourselves painted intoa corner. Nevertheless, the basic idea has served organic chemistry well. Note that

conversion of any compound to another in the same category is not an oxidation ora reduction. Most oxidations in organic chemistry involve a gain of oxygen and/or a loss of hydrogen (Lavoisier’s original definition of oxidation). The reverse is true for reductions.

Of course, there is no oxidation without a concurrent reduction. However,we classify reactions as oxidations or reductions depending on whether theorganic compound is oxidized or reduced.

Eliminations of Hydrogen

Aromatization of Six-Membered Rings

Hexahydro-terelimination

Alicyclic (Of or relating to organic compounds having both aliphatic and cyclic characteristics or structures)

Six-membered alicyclic (Of or relating to organic compounds having both aliphatic and cyclic characteristics or structures) rings can be aromatized in a number of ways.

Aromatizationis accomplished most easily if there are already one or two double bonds in the ring or if the ring is fused to an aromatic ring. The reaction can also be appliedto heterocyclic five - and six-membered rings. Many groups may be present on thering without interference, and even gem-dialkyl (In chemistry, the term geminal (from Latin gemini = twins) refers to the relationship between two functional groups that are attached to the same atom. The prefix gem is applied to a chemical name to denote this relationship, as in a gem-dibromide) substitution does not always preventthe reaction). In such cases, one alkyl group often migrates or is eliminated.

However, more drastic conditions are usually required for this. In some cases

OH and COOH groups are lost from the ring. Cyclic ketones are converted to phenols.Seven-membered and larger rings are often isomerized to six-membered aromaticrings, although this is not the case for partially hydrogenated azulene systems(which are frequently found in Nature); these are converted to azulenes.

There are three types of reagents most frequently used to effect aromatization.

1. platinum, palladium and nickel Cyclohexene has been detected as an intermediate in the conversion

of cyclohexane to benzene, using Pt. The substrate is heated with thecatalyst at _ 300–350_C. The reactions can often be carried out under milder conditions if a hydrogen acceptor, such as maleic acid, cyclohexene, or benzene, is present to remove hydrogen as it is formed. The acceptor isreduced to the saturated compound. Other transition metals can be used,including TiCl4-NEt3 For polycylic systems, heating with oxygen on activated carbon generates the aromaticcompound, as in the conversion of dihydroanthracene to anthracene.

dihydroanthracene

2. The elements sulfur and selenium, which combine with the hydrogen evolved to

give, respectively, H2S and H2Se.

3. Quinones,21 which become reduced to the corresponding hydroquinones. Two

important quinones often used for aromatizations are chloranil (2,3,5,6-tetrachloro-1,4-benzoquinone) and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone).

22 The latter is more reactive and can be used in cases where thesubstrate is difficult to dehydrogenate. It is likely that the mechanism involvesa transfer of hydride to the quinone oxygen, followed by the transfer of aproton to the phenolate ion.

Among other reagents that have been used for aromatization of six-memberedrings are atmospheric oxygen, MnO2 KMnO4-Al2O3, SeO2, various strong bases chromic acid, H2SO4 and a ruthenium catalyst,29 and SeO2 on P2O5/Me3SiOSiMe3.The last-mentioned reagent also dehydrogenates cyclopentanes to cyclopentadienes.

Heteroatom rings, as found in quinoline derivatives, for example, can be generatedfrom amino-ketones with [hydroxy(tosyloxy)iodo]benzene and perchloricacid or with NaHSO4-Na2Cr2O7 on wet silica.34 Dihydropyridines are convertedto pyridines with NaNO2–oxalic acid and wet silica35 BaMnO4, FeCl3–aceticacid, Mg(HSO4)2-NaNO2, or with nicotiniumdichromate. Cyclic imines are converted to pyridine derivatives with NCS, andthen excess sodium methoxide.

Dehydrogenations Yielding Carbon–Carbon Double Bonds

Dihydro-elimination

Dehydrogenation of an aliphatic compound to give a double bond in a specificlocation is not usually a feasible process, although industrially mixtures of alkenesare obtained in this way from mixtures of alkanes (generally by heating withchromia–alumina catalysts). There are, however, some notable exceptions. Heatingcyclooctane with an iridium catalyst leads to cyclooctene. Treating alkenes thathave an allylic hydrogen with CrCl2 converts them to allenes. It is not surprising,however, that most of the exceptions generally involve cases where the new doublebond can be in conjugation with a double bond or with an unshared pair of electronsalready present.

One example is the synthesis developed by Leonard andco-workers, in which tertiary amines give enamines when treated withmercuric acetate (see the example above). In this case the initial product is theiminium ion 1 which loses a proton to give the enamine. In another example, theoxidizing agent SeO2 can in certain cases convert a carbonyl compound to ana,b-unsaturated carbonyl compound by removing H2 (though this reagent moreoften gives). This reaction has been most often applied in the steroid series,an example being formation of 2 from 3. In a similar manner, Hunig’s base, dii-sopropylethylamine, was converted to the enamine N,N-diisopropyl-N-vinylamineby heating with an iridium catalyst.

Ph(S=O)OMe and KH, and also with (pyridyl)S(=O)OMe/KH, and thenCuSO4.53 Silyl enol ethers also give the conjugated ketone upon treatment withceric ammonium nitrate in DMF54 or with Pd(OAc)2/NaOAc/O2. Simple aldehydesand ketones have been dehydrogenated (e.g., cyclopentanone ! cyclopentenone)by PdCl2, by FeCl3, and by benzeneseleninic anhydride58 (this reagentalso dehydrogenates lactones in a similar manner), among other reagents.In an indirect method of achieving this conversion, the silyl enol ether of a simpleketone is treated with DDQ or with triphenylmethyl cation. Simple linear alkanes have been converted to alkenes by treatment with certain transition-metal compounds,

An entirely different approach to specific dehydrogenation has been reported byR. Breslow62 and by J.E. Baldwin.63 By means of this approach it was possible, forexample, to convert 3a-cholestanol (4) to 5a-cholest-14-en-3a-ol (5), thus introducinga double bond at a specific site remote from any functional group.64 This was accomplished by conversion of 4 to the ester 6, followed by irradiation of 6, which

gave 55% 8, which was then hydrolyzed to 5. The radiation excites the benzophenone portion of 6, which then abstracts hydrogen from the 14 position to give the diradical 7, which undergoes another internal abstraction to give 8.

Oxidation or Dehydrogenation of Alcohols to Aldehydes and Ketones

C,O-Dihydro-elimination

Primary alcohols can be converted to aldehydes and secondary alcohols to ketonesin seven main ways;

1. With Strong Oxidizing Agents

Secondary alcohols are easily oxidized toketones by acid dichromate71 at room temperature or slightly above. Many other strong oxidizing agents (KMnO4,72 ruthenium tetroxide,73 etc.) have also been employed. A solution of chromic acid and sulfuric acid in water isknown as the Jones reagent. When secondary alcohols are dissolved inacetone, titration with the Jones reagent oxidizes them to ketones rapidly andin high yield without disturbing any double or triple bonds that may bepresent and without epimerizing (In chemistry, epimers are diastereomers that differ in configuration of only one stereogenic center) an adjacent stereogenic center.

Epi Inositol Inositol

Reagents involved are pyridinium chlorochromate (PCC), and pyridiniumdichromate (PDC).

2. The Oppenauer Oxidation.

When a ketone in the presence of an aluminumalkoxide is used as the oxidizing agent (it is reduced to a secondary alcohol),the reaction is known as the Oppenauer oxidation.155 This is the reverse of theMeerwein–Ponndorf–Verley reaction (19-36) and the mechanism is also thereverse. The ketones most commonly used are acetone, butanone, andcyclohexanone. The most common base is aluminum tert-butoxide. The chiefadvantage of the method is its high selectivity. Although the method is mostoften used for the preparation of ketones, it has also been used for aldehydes.An iridium catalyst156 has been developed for the Oppenauer oxidation, andalso a water-soluble iridium catalyst.

3. With DMSO-Based Reagents

An alcohol is treated with DMSO, DCC, andanhydrous phosphoric acid160 in what is called Moffatt oxidation. In this way,a primary alcohol can be converted to the aldehyde with no carboxylic acidbeing produced. The strong acid conditions are sometimes a problem, andcomplete removal of the dicyclohexylurea by-product can be difficult. Theuse of oxalyl chloride and DMSO at low temperature, the Swern oxidation,161is generally more practical and widely used. Maintaining the low reaction

temperature is essential in this reaction however, since the reagent generatedin situ decomposes at temperatures significantly below ambient.

(N,N'-Dicyclohexylcarbodiimide)DCC

TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl, or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl or TEMPO is a chemical compound with the formula (CH2)3(CMe2)2NO )

TEMPO

Other nitroxyl radical oxidizing agents are known.195 A related oxidizing agent isoxoammonium salt 12 (Bobbitt’s reagent), a stable and nonhygroscopic saltthat oxidizes primary and secondary alcohols in dichloromethane

5. With Hypervalent Iodine Reagents

Treatment of 2-iodobenzoic acid withKBrO3 in sulfuric acid and heating the resulting product to 100_C with aceticanhydride and acetic acid gives hypervalent iodine reagent 13, the so-calledDess–Martin Periodinane.198 This reagent reacts with alcohols at ambienttemperature to give the corresponding aldehyde or ketone.199 The reaction isaccelerated by water200 and a water-soluble periodinane (o-iodoxybenzoic acid,14) has been prepared that oxidized allylic alcohols to conjugated aldehydes.

The reagent has an indefinite shelf-life in a sealed container, but hydrolysisoccurs upon long-term exposure to atmospheric moisture. A note of CAUTION!The Dess–Martin reagent can be shock sensitive under some conditions andexplode >200_C.202 Other hypervalent iodine oxidizing reagents areknown,203 including PhI(OAc)2/TEMPO,204 PhI(OAc)2–chromium salen,205stabilized iodoxybenzoic acid,206 and PhI(OAc)2 supported on alumina withmicrowave irradiation.207 Microwave irradiation of benzylic alcohols withPhI(OH)OTs gave the corresponding aldehyde.208 Hypervalent iodine compounds

have been used in ionic liquids.209 Heating benzylic alcohols with oiodoxybenzoicacid under solvent-free conditions gave the aldehyde.210Cyclopropylcarbinyl alcohols are oxidized to the corresponding cyclopropylketone or aldehyde with PhIO and a chromium–salen catalyst.211 The Dess–Martin reagent oxidized aryl aldoximes to aryl aldehydes.

6. By Catalytic Dehydrogenation

For the conversion of primary alcohols toaldehydes, dehydrogenation catalysts have the advantage over strong oxidizingagents that further oxidation to the carboxylic acid is prevented. Copperchromite is the agent most often used, but other catalysts (e.g., silver andcopper) have also been employed. Many ketones were prepared in thismanner. Catalytic dehydrogenation is more often used industrially than as alaboratory method. However, procedures using copper oxide,213 copper(II)complexes,214 rhodium complexes,215 ruthenium complexes,216 Raney

nickel,217 and palladium complexes218 (under phase-transfer conditions).

have been reported. Allylic alcohols220 are oxidized to the correspondingsaturated aldehyde or ketone by heating with a rhodium catalyst, and benzylicalcohols are converted to the aldehyde with a rhodium catalyst.221 Photolysiswith an iron catalyst gives similar results.222 Propargylic alcohols areoxidized by heating with a vanadium catalyst.223 Secondary alcohols are

oxidized with Bi(NO3)3 on Montmorillonite (Montmorillonite is a very soft phyllosilicate group of minerals that typically form in microscopic crystals, forming a clay. It is named afterMontmorillon in France.).

7. Miscellaneous Reagents

Nitric acid in dichloromethane oxidizes benzylicalcohols to the corresponding ketone. 226 Bromine is an effective oxidant, andiodine under photochemical conditions has been used.227 Heating a 1,2-diol

with NBS in CCl4 gave the 1,2-diketone.228 N-Bromosuccinimide with bcyclodextrinoxidizes tetrahydropyranyl ethers in water.229 Iodine has beenused in conjunction with DMSO and hydrazine.230 Sodium bromate (NaOBr)in conjunction with HCl oxidizes a-hydroxy esters to a-keto esters.231Enzymatic oxidations have been reported.232 Dimethyl dioxirane233 oxidizesbenzylic alcohols to the corresponding aldehyde,234 and dioxirane reagentsare sufficiently mild that an a,b-epoxy alcohol was oxidized to the correspondingketone, without disturbing the epoxide, using methyl trifluoromethyldioxirane.235 Hydrogen peroxide with urea oxidizes aryl aldehydes informic acid.236 Potassium monoperoxysulfate in the presence of a chiral ketone oxidizes 1,2-diols to a-hydroxy ketones enantioselectively.237 Potassium monoperoxysulfate also oxidizes secondary alcoholsin the presence of O2.238 air in the presence of a zeolite oxidizes benzylicalcohols. 239 The reagent Brþ(collidine)2PF6 oxidizes benzylic alcohols tothe corresponding aldehyde.240 Sodium hypochlorite in acetic acid isuseful for oxidizing larger amounts of secondary alcohols.241 Calciumhypochlorite on moist alumina with microwave irradiation has been usedto oxidize benzylic alcohols.242 Chlorosulfimines, Ar(Cl)S____N__t-Bu,oxidize primary alcohols to aldehydes.243 This latter reagent is generatedfrom ArS-NHt-Bu and NCS.

What is so special about carbon that it should form so many compounds?The answer to this question came to August Kekule in 1854 during a London busride."One fine summer evening, I was returning by the last omnibus, 'outside' asusual, through the deserted streets of the metropolis, which are at other timesso full of life. I fell into a reverie and lo! the atoms were gambolling before myeyes. ... I saw how, frequently, two smaller atoms united to form a pair, how alarger one embraced two smaller ones; how still larger ones kept hold of three oreven four of the smaller; whilst the whole kept whirling in a giddy dance. I sawhow the larger-ones formed a chain. ... I spent part of the night putting on paperat least sketches of these dream forms." August Kekule", 1890.

"Organic chemistry nowadays almost drives me mad. To me it appears likea primeval tropical forest full of the most remarkable things, a dreadful endlessjungle into which one does not dare enter for there seems to be no way out.'*Friedrich Wohler, 1835.

"Wave mechanics has shown us what is going on, and at the deepest possiblelevel ... it has taken the concepts of the experimental chemist the imaginativeperception that came to those who had lived in their laboratories and allowed theirminds to dwell creatively upon the facts that they had found and it has shown hothey all fit together; how, if you wish, they all have one single rationale; and howthis hidden relationship to each other can be brought out.*' C. A. Coulson,London, 1951.

Reduction is the gain of electrons or a decrease in oxidation state by a molecule,

atom, or ion.

Though sufficient for many purposes, these descriptions are not precisely correct. Oxidation and reduction properly refer to a change in oxidation state — the actual transfer of electrons may never occur. Thus, oxidation is better defined as an increase in oxidation state, and reduction as a decrease in oxidation state. In practice, the transfer of electrons will always cause a change in oxidation state, but there are many reactions that are classed as "redox" even though no electron transfer occurs (such as those involving covalent bonds). Non-redox reactions, which do not involve changes in formal charge, are known as metathesis reactions.

The reactions in this section are classified into groups depending on the type of bond changeinvolved. These groups are (1) attack at carbon (C-O and C=O), (2) attack at noncarbonylmultiple bonds to heteroatoms, (3) reactions in which a heteroatom is removed from the substrate, (4) reduction with cleavage, (5) reductive coupling, and (6) reactions in which an organic substrate is both oxidized and reduced.

Attack at Carbon (C-O and C=O)(3)OC-seco-Hydro-de-alkoxylation (The names for all ring closing and ring opening transformations are based

on those of related acyclictransformations prefixed by ‘‘cycle'' for ring closings or “seco” for ring openings).

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