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Oxidations and Reductions:

Organic and biorganic processes.

Common Oxidants for Oxidation of Alcohols:

Transition Metals in a High Oxidation State

Chromium Oxidants

a) PCC (pyridinium chlorochromate)

               Used to oxidise primary alcohols to aldehydes - over-oxidation is rarely a problem.

               Secondary alcohols are readily oxidised to ketones.

               Relatively acidic reagent (more acid than PDC and Collins) - can cause problems with acid labile groups. Buffering the reaction with NaOAc can help.

 b) Collins' Reagent (CrO3 - pyridine)

               Used to oxidise primary and secondary alcohols to aldehdyes and ketones, respectively.

               Non-acidic reagent (mildly basic) - acid labile groups are tolerated.

               Requires a large excess of reagent for complete reaction.

 c) PDC (pyridinium dichromate)

               Less acidic than PCC and less basic than Collins' reagent

               Secondary alcohols are oxidised to ketones

               Primary alcohols can be oxidised to either aldehydes or carboxylic acids depending on the substrate and solvent:

 d) Jones Oxidation (aq. H2SO4, acetone, CrO3)

               Oxidises secondary alcohols to ketones

               Primary alcohols are oxidised to carboxylic acids

               Acidic reaction conditions are a problem with acid labile groups.

 Advantages of Chromium Oxidants

               Relatively mild conditions

               Easy work-up procedures

Disadvantages of Chromium Oxidants

               Work-up can be messy on large scale

               Often require a large excess of the Chromium reagent



Ruthenium Oxidants

TPAP (tetrapropylammonium perruthenate; Pr4NRuO4.

Chromium oxidants are usually used in stoichiometric quantities (and often in excess). A method which employs the transition metal oxidant in substoichiometric amounts is highly desirable for many reasons including atom economy (see later). TPAP is the most widely used of these reagents.

               N-methylmorpholine-N-oxide is used as the stoichiometric oxidant for recycling the catalyst.

               Primary alcohols are oxidised to aldehydes.

               Over-oxidation to the carboxylic acid is rare although can be induced by omitting the molecular sieves used to remove H2O from the reaction.

               Secondary alcohols are oxidised to the corresponding ketones

Primary alcohols react more rapidly than secondary alcohols - this can be exploited in a useful synthesis of lactones:


Manganese Oxidants

Manganese dioxide (MnO2)

               mild oxidant

               oxidises allylic, propargylic and benzylic alcohols (i.e. activated alcohols) to aldehydes or ketones:

Potassium Permanganate (KMnO2)

               A general and very powerful oxidant especially when used in aqueous solutions. Consequently not very chemoselective which limits its use.

               Can be used to oxidise the benzylic position of aromatic systems to carboxylic acids.

               The oxidising power of KMnO2 can be tempered by using the reagent in organic solvents.

               Biphasic conditions have also been used. A phase transfer catalyst such as BnNBu3+Cl is used to transfer the anionic oxidant into the organic phase.  

Dimethyl Sulfoxide-Activated Oxidations

There are a wide variety of oxidation methods based on activation of DMSO. The most widely used is the so-called Swern oxidation:

               very mild method of oxidation

               over-oxidation to the carboxylic acid is not a problem

Hypervalent Iodine Oxidising Agents

There are a wide number of hypervalent iodine reagents (iodine in +3 and +5 oxidation state). The most important for oxidation purposes is Dess Martin Periodinane (DMP) so-named after its discoverers.

Readily prepared from 2-iodobenzoic acid:

               DMP is a very mild oxidant and is especially useful for oxidising molecules containing very sensitive functionality.

               Reaction conditions are either neutral or slightly acidic.

               Very chemoselective oxidising alcohols to aldehydes and ketones.

               Over-oxidation to the carboxylic acid is not a problem.

               Selectively oxidises alcohols in the presence of sulfides.  

Oxidation of Aldehydes to Carboxylic Acids

Sodium Chlorite (NaClO2)

               It is often more efficient to prepare a carboxylic acid from the alcohol in two steps proceeding through the aldehyde.

               Sodium chlorite (household bleach) is one of the mildest methods for achieving this:

               A by-product from this reaction is HOCl which is a good source of electrophilic chlorine. This may be a problem when the substrate also contains olefin functionality - add a more electron rich olefin such as resorcinol (1,3-dihydroxybenzene) which acts as an electrophile scavenger.

<TBODY> Alcohol to Aldehyde


 PDC (in CH2Cl2)

stoichiometric in Cr, neutral reaction conditions


stoichiometric in Cr, mildly acidic


stoichiometric in Cr, mildly basic


 catalytic in Ru







 Primary Alcohol to Carboxylic Acid


 PDC (in DMF)



 acidic reaction conditions


 usually suffers from lack of chemoselectivity

 Aldehyde to Carboxylic Acid





B. Epoxidation of Olefins

meta-Chloroperbenzoic acid (mCPBA)

General oxidant - electrophilic therefore reacts preferentially with electron rich C=C

Epoxidation of olefins is a syn-stereospecific process:

Rate of epoxidation is related to the nucleophilicity of the olefin - the more substituted or electron rich the more reactive: tetra/trisubstituted > disubstituted > monosubstituted olefins.

Regioselective Epoxidation

Diastereoselective Epoxidation

Steric hindrance is an important means for controlling the facial selectivity of reactions:


Directed Epoxidation

In non coordinating solvents, the hydrogen bonding capability of the peracid can be used to direct the epoxidation if there are hydrogen bond acceptor groups in close proximity to the olefin. This method can sometimes overcome the inherent steric bias of the substrate.

Example 1

Heteroatom Oxidation


Tertiary amines are readily oxidised to amine oxides

               Oxidation of chalcogens

Sulfides are readily oxidised to sulfoxides (over-oxidation to the sulfone can be a problem):

Selenides are even more readily oxidised to the corresponding selenoxides at low temperatures. Further oxidation is not a problem as the selenoxide readily undergoes stereospecific elimination on warming. This is a very useful method for preparing olefins.

An issue of chemoselectivity: competing reactions - Baeyer-Villiger Oxidation

Ketones react with mCPBA to form esters, (the Baeyer-Villiger reaction). In this case mCPBA is behaving as a nucleophile.

This is a useful reaction for preparing medium ring lactones by ring expansion.

The reaction is stereospecific proceeding with retention of configuration at the migrating centre.

The migratory preference is (approximately) of the order:
3 alkyl > 2 alkyl > alkenyl, phenyl > 1 alkyl > methyl


Dimethyldioxirane (DMDO)

Powerful and yet frequently selective electrophilic oxidant. Capable of oxidising very unreactive olefins. Reactions are carried out under mild conditions and the acetone by-product is inocuous and readily removed.

Detailed chemistry will be discussed.

Directed Epoxidation Reactions

Directed epoxidation reactions, as their name implies are reactions in which the reagent containing the oxygen that is to be transferred to the substrate is attached to the substrate through a non-covalent interaction (e.g. H bond or metal-ligand interaction). Typical substrates are allylic and homoallylic alcohols. The alcohol is critical for reaction to proceed efficiently and is therefore important in the reaction mechanism.

Vanadyl(acetylacetate) / tert-butylhydroperoxide (VO(acac)2/TBHP)

This combination of reagents will selectively epoxidise allylic alcohols in the presence of other (even more electron rich) olefins.

               TBHP oxidises VO(acac) 2 to a Vanadium(V) species which coordinates the alcohol of the substrate and the hydroperoxide.

               the vanadium centre can therefore be thought of as a template in which the reacting substrates are brought together allowing an intramolecular reaction to proceed.

               computational calculations have shown that the ideal O-C-C=C dihedral angle is 50 thus there are two possible reactive conformers:

In the case of homoallylic alcohols the selectivity can be rationalised by invoking a chair-like T.S. which maximises the number of equatorial substituents:


Sharpless Asymmetric Epoxidation

Titanium tetra-isopropoxide [Ti(Oi-Pr)4] can also be used in place of VO(acac)2 to effect a directed epoxidation of allylic alcohols. In the presence of a chiral ligand (such as diethyl tartrate) and under carefully optimised conditions, a catalytic enantioselective version was developed by Sharpless and is now known as the Sharpless Asymmetric Epoxidation (AE). Enantioselectivities are often in excess of 95% ee.

This is a very powerful reaction and can be applied to the majority of allylic alcohols. A useful cartoon has been developed to predict which ligand to use:

Again the proposed transition state has both the oxygen source (TBHP) and the substrate coordinated to a Titanium centre; the tartrate ligand creates the chiral environment.

Nucleophilic Epoxidation

So far all the methods of epoxidation require nucleophilic olefins and the more electron rich the better they react. Dr-Unsaturated carbonyl groups contain electron deficient olefins which are therefore poor substrates for these electrophilic reagents. However, by exploiting the potential nucleophilic character of peroxides it is also possible to epoxidise this type of double bond.

Alkaline Hydrogen Peroxide or Tert-Butylhydroperoxide

This combination of reagents generates a source of ROOG which is a good nucleophile.




<TBODY> Epoxidation Method

 Target Olefin

 electrophilic reagents:



electron rich olefins, allylic or homoallylic alcohols


electron rich olefins epoxidised preferentially but will epoxidise most olefins

 reagents requiring a directing group:


 VO(acac) 2 / TBHP

 good for allylic and homoallylic alcohols

 Ti(Oi-Pr)4 / TBHP / DET

Sharpless ASYMMETRIC epoxidation of allylic and homoallylic alcohols

 Nucleophilic reagents



Dr-unsaturated carbonyl systems</TBODY>


Oxidation of Olefins

Dihydroxylation of Olefins

Osmium Tetroxide (OsO4)

Osmium Tetroxide reacts under very mild conditions and extremely selectively with most olefins to provide the corresponding diol. OsO4 is an electrophilic reagent and therefore reacts most readily with electron rich olefins.

The reaction is stereospecific providing syn diol.

OsO4 is very expensive and highly toxic. However it can be used in catalytic amounts by employing a cheaper co-oxidant in stoichiometric quantities; the one most commonly used is N-methylmorpholine-N-oxide (NMO):

Observation: the rate of dihydroxylation is increased by the presence of tertiary amines - an example of Ligand Accelerated catalysis. Therefore by using CHIRAL tertiary amines there is the potential for developing an enantioselective version of the OsO4 dihydroxylation.

Sharpless Asymmetric Dihydroxylation

This is one of the most important and successful catalytic asymmetric process developed to-date. It is widely used, simple to carry out and is applicable to almost any alkene substrate. It is also relatively predictable in its outcome. The reaction is normally under REAGENT CONTROL i.e. the chiral ligand dictates the stereochemical outcome of the reaction irrespective of the chirality in the substrate.

The ligand, K2(CO3), K3Fe(CN)6 co-oxidant and source of osmium (K2OsO4 2H2O) are commercially available as AD-mix D (contains DHQ ligand) or AD-mix r (contains DHQD ligand) - just need to add solvent and substrate!

Diol Cleavage

Lead(IV)Acetate (Pb(OAc) 4) and Sodium Periodate (NaIO4)

Both these reagents are capable of cleaving 1,2-diols to the corresponding carbonyl groups.
Thus the dihydroxylation / diol cleavage provides a two-step alternative to ozonolysis

A one-pot (see later for the importance of this type of process) OsO4 dihydroxylation - NaIO4 diol cleavage has been developed. The periodate has the added advantage of oxidising the Os(VI) back to Os(VIII) which allows the use of a catalytic quantities of OsO4:

Sodium periodate is a good reagent for oxidising sulfides to sulfoxide - the use of 1 eq. of periodate allows the isolation of the sulfoxide without competing over-oxidation to the sulfone.

Direct Oxidative cleavage of Olefins - Ozonolysis

               The reaction of ozone (O3) with olefins is the best method for the oxidative cleavage of double bonds.

               Mild and selective.

               O3 is an electrophilic reagent and therefore will react preferentially with electron rich double bonds.

               A variety of work-up procedures (cleavage of the ozonide intermediate) increases the versatility of this reaction:

Aromatic compounds can also be ozonolysed although they often require more forcing conditions (destroying the aromaticity). A furan may be viewed as a latent carboxylic acid (see later for masking strategies):

Ozonolysis generates the carboxylic acid

In Woodward's synthesis of strychnine, selective ozonolysis of the 1,2-dimethoxy aryl group released the (Z, E)-diene, an important synthetic intermediate.




Simple examples will be given. 

Note:  It is not possible to cover all reagents and reactions in this lecture.  Selection has been made on a personal note.

(Parts of this document are taken from web sites and edited). Thanks to the appropriate authors.


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Chemistry and Drug Discovery

Synthesis and anticancer activity of N-nitrosopiperidines

Though N-nitrosopiperidines are generally considered carcinogenic (inducing cancer) the degree of carcinogenicity depends on the conformational characteristics of N-nitrosamines. It decreases with twisting of the ring and introduction of the additional substituents at the a-position to the ring nitrogen atom. Simple N-nitrosopiperidine is a potent carcinogen. When one of the two -carbons is blocked by alkyl substituents, the nitrosamine becomes a moderate carcinogen. When both -positions are blocked by at least one alkyl group at each position the nitrosamine becomes a noncarcinogen. By invoking the principles of conformational analysis of piperidines and azabicyclic compounds that we have studied during the past four decades it was thought that the N-nitrosopiperidines might be possess anticancer properties. It has been found to be so indeed.

Contact Ramasubbu Jeyaraman :