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Transcript
III Semester M Sc-Organic synthesis via Oxidation and
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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
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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
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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).
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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
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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.
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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
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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:
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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
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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
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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
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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
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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
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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).
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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.
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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:
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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.
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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.
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