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Lithium aluminium hydride: explanation >

JONES REAGENT & ITS OXIDATION REACTIONS

* The Jones reagent is a mixture of chromic anhydride and dilute sulfuric acid (CrO3 + H2SO4 + H2O) in acetone. It is used in the oxidation of secondary alcohols, that do not contain acid sensitive groups, to corresponding ketones. * The primary alcohols are initially oxidized to aldehydes, which are finally oxidized to carboxylic acids. * A mixture of sodium dichromate or potassium dichromate in dilute sulfuric acid and acetone can also be used as Jones reagent.

* This oxidation is usually referred to as Jones oxidation.

Reaction conditions & Workup

* The Jones reagent is prepared by adding chromic anhydride to dilute sulfuric acid in acetone and is added to the alcohol at 0-25oC. * The orange or yellow colored Cr(VI) is reduced to blue green Cr(III) species during the oxidation. * The excess Cr(VI), if any is remained, is destroyed in the reaction workup by adding isopropyl alcohol.

MECHANISM OF JONES REACTION

* Initially, chromic acid(VI) is generated is situ from the mixture of chromic trioxide and dilute sulfuric acid.

* The alcohol and chromic acid form chromium (VI) monoester, which may react intramolecularly or inter-molecularly in presence of a base (H2O in this case) to give the corresponding carbonyl compound and chromium(IV) acid. The intra-molecular reaction occurs by way of a -elimination through a cyclic transition state.

* The aldehydes, which can form hydrates in presence of water can further undergo oxidation to yield carboxylic acids in Jones reaction.

* Hence oxidation of primary alcohols with Jones reagent usually results in the formation of carboxylic acids due to presence of water. However benzyl and allyl alcohols do not for hydrates in water and hence can be selectively oxidized to aldehydes. * If the oxidation is carried out in anhydrous conditions, it is possible to stop the reaction at aldehyde level. See at the end of the page for reagents which may serve this purpose. * Follow up chemistry of Cr(IV) :The chromium(IV) acid is disproportionated into Cr(III) oxide and Cr(VI) acid.

APPLICATIONS OF JONES REAGENT

1) The secondary alcohols are oxidized to corresponding ketones in Jones reaction.

2) The primary alcohols are oxidized to carboxylic acids via aldehydes with Jones reagent.

3) Benzyl alcohol can be oxidized to benzaldehyde. Further oxidation to benzoic acid is not possible as the benzaldehyde cannot form stable hydrates in water.

4) In Jones reaction, the allylic alcohols are also selectively oxidized to aldehydes. The double bonds are intact in this reaction.

Some oxidizing reagents containing Cr(VI)

1) Sarett reagent: CrO3.2C5H5N

(where C5H5N = pyridine)

2) Collins reagent: CrO3.2C5H5N diluted in CH2Cl2 3) Cornforth reagent: CrO3/ Pyridine / H2O 4) Fieser reagent: CrO3 in acetic acid. 5) Thiele reagent: CrO3 + acetic anhydride + H2SO4 6) Pyridinium Chlorochromate (PCC) in CH2Cl2 (Corey-Suggs reagent): [C5H5NH]+ [CrO3Cl]7) Pyridinium Dichromate (PDC) in CH2Cl2 or DMF (Corey-Schmidt reagent): (C5H5NH)2Cr2O7

Lithium aluminium hydride (LiAlH4 or LAH)

* Lithium aluminium hydride, LiAlH4, also abbreviated as LAH, is a reducing agent commonly employed in modern organic synthesis. * It is a nucleophilic reducing agent, best used to reduce polar multiple bonds like C=O. * LiAlH4 can reduce aldehydes to primary alcohols, ketones to secondary alcohols, carboxylic acids and esters to primary alcohols, amides and nitriles to amines, epoxides to alcohols and lactones to diols. * Lithium aluminium hydride cannot reduce an isolated non-polar multiple bond like C=C. However, the double or triple bonds in conjugation with the polar multiple bonds can be reduced. * LiAlH4 is a powerful reducing agent than sodium borohydride, NaBH4 since the Al-H bond is weaker than B-H bond.

Structure of Lithium aluminium hydride - LiAlH4

There is a tetrahedral arrangement of hydrogens around aluminium in aluminium hydride, AlH4- ion.

Preparation of LiAlH4
LiAlH4 is prepared by the reaction between lithium hydride and aluminium chloride.

Properties of LiAlH4 , Reaction conditions & Workup

* Lithium aluminium hydride is a white solid but the commercial samples are usually gray due to presence of impurities. * It reacts violently with water by producing hydrogen gas. Hence it should not be exposed to moisture and the reactions are performed in inert and dry atmosphere.

* The reaction must be carried out in anhydrous non protic solvents like diethyl ether, THF etc. It is highly soluble in diethyl ether. However it may spontaneously decompose in it due to presence of catalytic impurities. Therefore the preferred solvent for LAH is THF despite the low solubility. * The reactions are usually performed with excess of LiAlH4. A small amount of the reagent is added to the solvent to eliminate any moisture present in the solvent. Workup: During the workup, the reaction mixture is initially chilled in an ice bath and then the Lithium aluminium hydride is quenched by careful and very slow addition of ethyl acetate followed by the addition of methanol and then cold water. Sometimes, the reagent is decomposed by adding undried solvent slowly and then dilute sulphuric acid to the reaction mixture.

MECHANISM OF REDUCTION BY LITHIUM ALUMINIUM HYDRIDE

* The reduction of a carbonyl group by LiAlH4 is initiated by the attack of nucleophilic hydride ion on the carbonyl carbon to give a tetrahedral intermediate. * LiAlH4 is a nucleophilic reducing agent since the hydride transfer to the carbonyl carbon occurs prior to the coordination to the carbonyl oxygen. It reacts faster with electron deficient carbonyl groups. The reactivity of carbonyl compounds with this reagent follows the order: Aldehydes > Ketones > ester > amide > carboxylic acid * The steps involved in the reduction of various functional groups are shown below: Reduction of Aldehydes or Ketones to 10 or 20 alcohols: Initially, a hydride ion is transferred onto the carbonyl carbon and the oxygen atom coordinates to the remaining aluminium hydride species to furnish an alkoxytrihydroaluminate ion, which can reduce the next carbonyl molecule. Thus three of the hydride ions are used up in reduction.

Reduction of Esters to 10 alcohols: The ester is first converted to aldehyde which is further reduced to primary alcohol.

Reduction of Amides to amines: Amides are converted to amines. The mechanism is slightly different from that depicted for esters. In iminium ion is formed during the reaction since nitrogen atom is relatively a good donor than oxygen atom.

Reduction of nitriles to primary amines:

APPLICATIONS OF LiAlH4
The summary chart of applications of LiAlH4 in the reduction of different types of functional groups. Functional group conversion Aldehydes, ketones -------> Alcohols Carboxylic acids -------> Alcohols Esters, acid halides -------> Alcohols Amides -------> amines Nitriles -------> amines oxiranes (epoxides) -------> alcohols lactones -------> diols haloalkanes, haloarenes -------> alkanes, arenes equivalents of LiAlH4 1 3 2 2 2 1 2 1

1) The aldehydes or ketones are reduced by LiAlH4 to the corresponding primary or secondary alcohols respectively. E.g. Acetaldehyde is reduced to ethyl alcohol and acetone is reduced to isopropyl alcohol.

* LiAlH4 does not affect the isolated carbon-carbon double or triple bonds.

*However, the double bonds in conjugation at , positions of carbonyl group may also be reduced by Lithium aluminium hydride depending on the reaction conditions. E.g. Cinnamaldehyde is reduced to Hydrocinnamyl alcohol when reduced with excess of LiAlH4 (roughly more than 2 equivalents) by normal addition method. In this method, a solution of cinnamaldehyde is added to the solution of lithium aluminium hydride. Both the double bond and carbonyl group are reduced.

Whereas, Cinnamaldehyde is reduced to Cinnamyl alcohol with one equivalent of LiAlH4 in inverse addition method. In this method, the solution of LiAlH4 is added to the solution of Cinnamaldehyde. Only the carbonly group is reduced to alcohol.

Stereochemistry: The axial attack of hydride ion is preferred over the equatorial attack in case of cyclic systems. For example, 4-t-butylcyclohexanone yields more than 90% of trans-4-tbutylcyclohexanol when reduced with Lithium aluminium hydride.

The plausible explanation for this behavior is: the -OH group prefers the equatorial position to avoid the interactions with other axial hydrogens. i.e., It is not the approach of hydride ion but the orientation of -OH group which decides the final stereochemistry. 2) The carboxylic acids, esters and acid halides are reduced to corresponding primary alcohols by Lithium aluminium hydride. E.g. The reduction of Acetic acid, methyl acetate and acetyl chloride by LiAlH4 furnish the same ethyl alcohol.

3) The amides are reduced to amines by LAH. Especially this method is used to get secondary amines. E.g. Diethyl amine can be prepared starting from acetyl chloride as follows:

4) The nitriles are reduced to primary amines by LiAlH4. E.g. Acetonitrile is reduced to ethyl amine by LiAlH4.

5) Lithium aluminium hydride reduces the oxiranes (epoxides) to alcohols. The hydride attack occurs at less hindered side of the epoxide. E.g. 2-methyloxirane gives 2-propanol predominantly.

In case of cyclohexene epoxides, the axial alcohols are formed preferentially. E.g.

6) The lactones are reduced to ,-diols by Lithium aluminium hydride. E.g.

7) The haloalkanes and haloarenes are reduced to corresponding hydrocarbons by LiAlH4.

Pyridinium Dichromate (PDC)

* Pyridinium dichromate (PDC), (C5H5NH)2Cr2O7 is an orange colored solid used as an oxidizing agent. * PDC is less acidic than PCC ( PyridiniumChloroChromate) and hence is more suitable in the oxidation of acid sensitive compounds. * PDC in CH2Cl2 or DMF is also called as Corey-Schmidt reagent. In this case, PDC is maintained in anhydrous conditions. * It is used for the selective oxidation of allylic alcohols in presence of other alcoholic groups. The oxidation product also depends on the solvent used. In Dichloromethane, it conveniently oxidizes primary alcohols to aldehydes at room temperature. Whereas, in DMF, a polar solvent, the non-conjugated primary alcohols are oxidized to carboxylic acids. However conjugated alcohols like allylic and benzylic primary alcohols always give aldehydes only even in DMF.

Note: A mixture of CrO3, pyridine and water, which also forms PDC, is known as Cornforth reagent. This reagent contains water along with PDC. Hence it cannot be used in controlled oxidation of primary alcohols to aldehydes. However it can be used to oxidize secondary alcohols to ketones.

Structural Formula & Preparation

* Pyridinium dichromate, PDC can be obtained by gradual addition of a solution of chromic anhydride (CrO3) in water to pyridine in ice cold conditions.

However, the addition of anhydrous CrO3 to pyridine in ice cold conditions give dipyridine chromium(VI) oxide, CrO3.2C5H5N also called as Sarett's reagent. Properties of reagent, Reaction conditions & Workup Properties: * Commercially, Pyridinium dichromate (PDC) is available as an orange solid. It is non hygroscopic. It is unaltered in open air. * It is soluble in water, DMF and DMSO. But sparingly soluble in CH2Cl2 or CH3Cl. Reaction condtions: * The reaction conditions are mild and neutral. It can be employed to oxidize compounds containing acid sensitive functional groups. * Even though the pyridinium cations are slightly acidic, very acid sensitive functionalities can withstand the action of PDC. However, some sodium acetate can be added as a buffer for a completely acid-free oxidations. * The reactions are usually slow and some accelerators are needed. The activated molecular sieves; organic acids like acetic acid, pyridinium trifluoroacetate (PTFA), pyridinium tosylate (PPTS) etc.; acetic anhydride are added to speed up PDC oxidations. * Anhydrous conditions must be maintained strictly to avoid the formation of carboxylic acids. The solvent CH2Cl2, can be dried over PDC and may be stored over molecular sieves to get best results.

Workup: * The final workup involves addition of diethyl ether and the precipitate (inorganic part) is decanted and washed with ether. The collected organic phases are filtered through a pad of Celite or Silica or Fluorisil. Then the organic phase is concentrated to get the final product, which may be further purified by chromatographic techniques. Alternately, Diethyl ether is added to the reaction mixture and washed with aqueous solutions of NaHCO3, HCl or NaCl. Then the ether phase is dried over MgSO4 or NaSO4 and concentrated to get the final residue which may need further chromatographic purification. * Chromium (VI) compounds are carcinogenic and hence must be handled with care.

MECHANISM
* For the details of mechanism refer to jones reagent.

APPLICATIONS
* Primary alcohols are conveniently oxidized to aldehydes with Pyridinium dichromate, PDC in dichloromethane at room temperature.

* Acid sensitive groups, such as enol ethers, are not affected during the oxidation with PDC.

* Non-conjugated primary alcohols are oxidized to carboxylic acids with excess of PDC in moist DMF. But in Dichloromethane, the oxidation stops at aldehyde level only.

* However the conjugated primary alcohols are only oxidized to aldehydes even in DMF.

* The secondary alcohols are oxidized to ketones with Pyridinium dichromate, PDC.