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Paper No and Title 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2)

Module No and Title 16: Reduction by Metal – Part-I

Module Tag CHE_P9_M16

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

TABLE OF CONTENTS

1. Learning Outcomes 2. Introduction 3. Reduction methods 3.1 Catalytic resuctions 3.2 Electroreductions and metal reductions 3.3 and complex hydride reductions 3.4 Reduction with non-metal compounds 3.5 Reduction by organic compounds 4. Hetero atom-carbon multiple bond reduction by metal hydride 4.1 Reduction of Saturated carbonyl compounds 4.1.1 Reduction by Hydride from NaH, NaBH4 and LiAlH4 5. Summary

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

1. Learning Outcomes

After studying this module, you shall be able to

 Familiar with an overview of different categories of reductions  Understand the reduction via hydride transfer by the use of hydride and boronhydride reagents.  Differentiate between the selectivity and reactivity of LiAlH4 and NaBH4  Be familiar with other reducing agents viz., sodium cyanoborohydrin,(NaBH3CN), diisobutylaluminium hydride (DIBAL), (B2H6) and super hydride i.e. Lithium triethylborohydride (LiEt3BH).  Comprehend how the heteroatom-carbon multiple bond reduction takes place by metal hydrides for carbonyl compounds

2. Introduction

Oxidation-reduction reactions are vital for biochemical reactions and industrial processes. The reaction includes the electron transfer system in cells and oxidation of glucose in the human body. Redox reactions are typically used to reduce ores in order to obtain metals to name a few applications of reduction.

Reduction is generally done either by catalytic or reduction by metal hydrides. Catalytic hydrogenation is achieved by the addition of molecule to the compound under the influence of a catalyst. The reduction by metal hydrides, on the other hand, is carried out by transferring hydride from the metal hydrides to the substrate. Many reducing agents are available, but our main focus of study in this module remains metal hydrides.

A hydride is basically an anion of hydrogen (H−, hydride ion) or more commonly, an alloy, or compound having one or more centres of hydrogen having nucleophilic, reducing or basic properties. In hydrides, the hydrogen is linked by more electropositive element or group. They are known for their reducing properties.

The two well- known hydrides are lithium aluminium hydride (LiAlH4) and sodium (NaBH4). They contain polar metal-hydrogen linkage because of less electronegativity of aluminium than that of boron, making them stronger reducing agents. Few other examples of reducing agents that contain hydrides in them and are commonly used as reducing agents in chemical synthesis are:

 di-isobutyl aluminium hydride (DIBAL) i.e., (i-Bu2AlH)2 where i-Bu represents isobutyl [-CH2CH(CH3)2].  Sodium cyanoborohydrin (NaBH3CN)  Super hydride i.e., Lithium triethylborohydride (LiEt3BH)  diborane (B2H6) CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

The reduction reactions achieved by metal hydrides involve carbon– double bonds, carbon– double bonds, and the carbon–nitrogen triple bond. The mechanism involved here is very easy as compared to that of the additions to carbon–carbon multiple bonds. As the double bond of carbon-oxygen and carbon-nitrogen triple bonds are strongly polar due to electronegative oxygen and nitrogen respectively, the carbon always is at the positive terminal (except for isocyanides). Hence, the orientation of unsymmetrical addition to these bonds is very obvious. Nucleophilic attacking species always gets attached at the carbon and electrophilic species to the oxygen or nitrogen.

Keeping these things in mind, let us discuss the reaction of carbon–oxygen, carbon–nitrogen double bonds, and the carbon–nitrogen triple bond one by one. Here we shall discuss the hydride reduction of carbonyl compounds only. The hydride reduction of carboxylic acids, their derivatives and shall be discussed in next module.

3. Reduction methods

Reduction in simple terms, indicates the addition of hydrogen to a molecule. A very common reduction example is the reduction of to primary . For example: propanal is reduced to propanol when reduced by hydrogen gas in the presence of a platinum catalyst.

Before studying about the hydride reducing agents in detail, let us be familiar about different methods of reduction, which are as follows:

3.1 Catalytic reductions: As the name suggests, it is the reduction with the help of catalysts. Here hydrogen is added to multiple bonds in the presence of catalysts like Pt, Ni, Pd etc. The choice of metal catalyst depends upon the compound to be used. Hydrogen gets adsorbed on the catalyst surface and hydrogen addition takes place in the form of radical i.e., in all the catalytic reduction: 2e- and 2H+ are added as two H. radicals. This addition is sterically controlled and leads to syn addition. Catalytic are totally chemoselective and are often chosen for this purpose over other methods of reduction.

 Palladium and platinum are the most commonly used metal catalysts for hydrogenation.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

On the contrary, hydrogenation can also work with nickel, rhodium or ruthenium.

Substrate Usual choice of metal Benzyl or Pd Pd, Pt or Ni Aromatic ring Pt or Rh or Ni under high pressure

 Temperature condition greatly affect the hydrogenation of various functional groups. At lower temperatures, if two functional groups present in the same molecule, like carbonyl and alkene double bond, only alkene is reduced and carbonyl remains unchanged.

But at higher temperatures, both alkene and carbonyl get reduced to and alcohols

Important metal reduction reactions and reducing agents have been enlisted below:

 Rosenmund reaction: It is a well known hydrogenation reaction in this category. Hydrogenation of acyl chlorides yielding aldehydes is known as Rosenmund reaction. This is good reaction for reducing compounds like to their corresponding aldehydes.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

 Lindlar’s catalyst: This catalyst reduces the to The Lindlar’s catalyst is a Palladium catalyst deliberately poisoned with lead (Pd/CaCO3). The lead lessens the activity of the catalyst and makes further reduction of the alkene product slow.

 Adam’s catalyst: Adam’s catalyst is formally PtO2. This catalyst is not an oxide of platinum, but the platinum metal that forms by reduction of PtO2 to Pt during the hydrogenation.  Raney Nickel: This catalyst is often abbreviated as RaNi and it is a finely divide form of nickel made from a nickel-aluminium alloy. The aluminium is dissolved away using concentrated aqueous sodium leaving the nickel as a fine powder.

3.2 Electroreductions and Metal reductions-In this category of reduction, the metal gives an electron and solvent gives a proton i.e. 2e- and 2H+ are added alternately step by step as e- , H+ , e- , H+. This is thermodynamically controlled reaction. Many metals have been used like, Na, Mg, Zn, Sn, etc in the presence of or acid as reducing agents. Birch reductions is one of the well-known examples of such type of reductions.

Birch reduction: The reduction of double bond systems using dissolved metal like lithium, sodium in liquid is called Birch reduction. The solvated electrons obtained from the easily ionisable Group 1 metals in ammonia are employed as reducing agents. This reaction is regiospecific.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

Birch reduction works for alkynes too, and is a good way of reducing them to trans double bonds (cis products are obtained by using Lindlar’s catalyst).

Note: Phenols and isolated double bonds are not reduced by this method.

Some examples of such reductions are drawn below:

 Reduction of benzene rings

 Reduction of alkynes to trans alkenes

 Reduction of by sodium

3.3 Hydride and complex hydride reductions-In hydride reduction, the hydrogen addition takes place as hydride ion followed by proton i.e. as H- and H+. The hydride is donated by metal hydrides.

For example, aldehydes and can be reduced by NaBH4 or LiALH4 into corresponding alcohols.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

3.4 Reduction with non-metal compounds

Reductions have also been carried out by non-metal compounds such as HI, hydrogen sulphide, ammonium sulphides, diimide, , etc. as reducing agents.

3.5 Reduction by organic compounds

These reductions are carried by using organic compounds such as alcohols, organometallic compounds etc. as reducing agents.

Of these different categories of reductions, we shall focus our study on Hydride reduction in this module.

Most common Metal Hydrides: LiAlH4 and NaBH4

Sodium borohydride and lithium aluminium hydride are the most common hydride reagents.

Schlesinger and Brown and their coworkers, mentioned the synthesis and some applications of LiAlH4 for the reduction of organic compounds, in 1947.

 LiAlH4 is prepared by the reaction of (LiH) with (AlCl3). CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

 Sodiumborohydride is prepared by the reaction of (NaH) with trimethylborate, B(OMe)3

There is difference in the reactivity of Sodium borohydride and lithium aluminium hydride.

Sodium borohydride Lithium aluminium hydride Boron being part of second period makes Aluminium being part of third period makes shorter and stronger bond with hydrogen longer and weaker bond with hydrogen. The B-H bond of NaBH4 has more covalent The Al-H bond has more ionic character in character LiAlH4 It is less reactive It is more reactive It is a weak It is a stronger base

Lithium aluminum hydride (LiAlH4) is known to be a powerful reducing agents for organic compounds having polarizable . They are stable at any temperature but with moisture it get converted into hydrogen gas, lithium hydroxide and aluminum hydroxide (hydrated alumina)

The LiAlH4 reagent is usually stable at normal temperature but in the presence of moisture, it is destroyed as the following reaction take place.

LiAlH4 + 4 H2O  LiOH + Al(OH)3 + 4 H2

Hence reactions are carried out in ethereal solvents like THF or ether.

4. Hetero atom-carbon multiple bond reduction by metal hydrides.

In general, reductions of functional groups encompass a range of reaction types and are classified into groups depending on the type of bond undergoing reduction. These groups are carbonyl, acids, esters and nitriles. In this module, we shall focus on the compounds having carbonyl groups.

4.1 Reduction of carbonyl compounds

Carbonyl compounds give variety of useful derivatives. You are already familiar that they mostly undergo nucleophilic addition reactions in which a nucleophile and a proton are added to the carbonyl double bond. In the carbonyl group, the oxygen atom is electronegative and this results CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

in the carbon-oxygen double bond polarization. Due to this polarized nature of the carbonyl group, it is very reactive. The electrophilic carbon atom of the carbonyl group is sp2 hybridized and flat, leaving it relatively unhindered and open to attack from either face of the double bond.

4.1.1 Reduction by Hydride from NaH, NaBH4 and LiAlH4

A negatively charged atom like hydride ion can act both as nucleophile and as a base. Whether a hydride ion (H:-) will act as a nucleophile or a base depends on the reagent used. – Let us consider the H generating from the metal hydrides NaH, NaBH4 and LiAlH4 one by one.

a. Sodium hydride (NaH): Sodium hydride is an ionic compound. H– from NaH is very small in size and has high charge density. It only reacts as a base and not as a nucleophile. This is because the contribution of hydrogen atom to the σ* orbitals of the H–X bond (where X is any atom) and the filled 1s orbital is ideal for interaction. Instead of this, 1s orbital which is filled is very small to link with carbon’s more diffuse 2p orbital contribution to the LUMO (π*) of the C=O group.

Adding H– to the carbon atom of a C=O group would yield an alcohol and shall be a very helpful reaction. But, the to alcohol cannot be done with NaH. So what can be added to achieve this? The simplest answer is NaBH4 or LiAlH4.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

– b. Sodium borohydride (NaBH4): It is a water-soluble salt that contains tetrahedral BH4 anion, – which is isoelectronic with . There is a negative charge on BH4 . This is because, boron contains one less proton in the nucleus than does carbon (analogous CH4 is neutral).

Though no hydride ion, H–, is actually involved in the reaction, the transfer of an atom of hydrogen with an attached electrons pairs can be regarded as a ‘hydride transfer. In other – words, from BH4 , one of the H with the electron pair gets transferred. Note that it is the hydrogen atom that forms the new bond to C. This reaction may be illustrated with a curly arrow passing through the hydrogen atom.

The oxyanion produced in the intial step helps stabilize the electron-deficient BH3 molecule by adding to its empty p orbital. As a result, a tetravalent boron anion is produced again, which in turn transfers a second hydrogen atom (with its pair of electrons) to another molecule of .

This process can continue, in principle, so that all four atoms of hydrogen could be transferred to molecules of aldehyde one by one. But in practice, all the four atoms of hydrogen are not transferred. The first step is carried out in the presence of ethereal solvents like THF and . The water (or alcohol) added in subsequent step to work up provide the proton required for the formation of the alcohol from the alkoxide ion in the last step.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

Sodium borohydride reduces both aldehydes and ketones, though the reaction with ketones is slower. For example, benzaldehyde is reduced about 400 times faster than acetophenone in iso- propanol as solvent.

Sodium borohydride is one of the weakest hydride donors available. In fact, almost no reaction with water is evidence of this, else it would have combined with water where H- would have acted as base.

Specificity: Sodium borohydride is a specific reagent and does not attack of carbon-carbon double or triple bonds of alkenes and alkynes respectively as they are not sufficiently polarised. If multifunctional groups are there like carbonyl, alkene, and etc. in a molecule, it reduces aldehyde and functional groups only.

Example: In the following molecule having ketone, alkene and ester; only ketonic group is reduced to alcoholic group. The carbon-carbon double bonds and ester functional groups are unaffected.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

There can be steric approach to control reaction. e.g., reduction of norcamphor. In this case, the less sterically hindered exo attack is dominant, giving rise to endo-alcohol as the major product.

c. Lithium aluminium hydride (LiAlH4): In contrast to sodium borohydride, lithium aluminium hydride is a strong hydride donor and combines rapidly with water.

Lithium aluminium hydride (LiAlH4) is more electropositive (more metallic) than boron in NaBH4. The hydride from LiAlH4 is therefore more electron rich and thus is a stronger base (in reaction with water) and stronger nucleophile (with carbonyl group).

 Basic action: In the basic action of hydride, Lithium aluminium hydride reacts violently and dangerously with water in an exothermic reaction that produces highly flammable hydrogen.

 Nucleophilic action: In its nucleophilic action of hydride, LiAlH4 reduces all type of carbonyl groups viz., in aldehyde, ketones, esters, carboxylic acids and . Aldehydes and ketones are reduced to primary and secondary alcohols respectively.

Mechanism of reduction by LiAlH4:

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

Groups not affected by LiAlH4: Other functional groups like nitro or halides are not reduced by LiAlH4.

Other Metal Hydrides: When the hydrogen of LiAlH4 or NaBH4 is replaced by either alkyl or alkoxy group, they lead to the formation of variety of reducing agents.

Since LiAlH4 is a powerful reagent, it is much less chemoselective than most of the other metal hydrides. Consequently, other metal hydrides are generally used when chemoselectivity is desired. In order to achieve chemoselectivity, a number of less reactive (and more selective) reagents have been prepared by replacing some of the hydrogen atoms of LiAlH4 with alkoxy groups. This is done by treatment of LiAlH4 with ROH. Most of these hydrides of metals are nucleophilic reagents and attack on the carbon atom of the carbon-hetero single or multiple bond.

Example: By enhancing the metal hydride into NaCNBH3, ammonia mediated reductive introduction of amine group to aldehydes to produce primary was specifically achieved without the occurrence of by product of secondary and tertiary amine.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I

In general, it is always better to use the mild conditions possible for any particular reaction to reduce the potential for unwanted side reactions. Reduction with NaBH4 is a lot easier to handle than LiAlH4—for example, it simply dissolves in water while LiAlH4 catches fire if it gets wet. Hence, NaBH4 is usually commonly used to reduce aldehydes and ketones, even though LiAlH4 also works but proper handling is required.

5. Summary

 In general, reduction can be achieved by catalytic hydrogenation, or with metals or with metal hydrides or with organic compounds as reducing agents.  Commonly used metal hydrides are lithium aluminium hydride and sodium borohydride.  LiAlH4 is known to be a powerful and comparatively nonselective hydride-transfer reagent. It reduces carboxylic acids, esters, , anhydrides to the corresponding alcohols and reduces amides and nitriles to the corresponding amines. Aldehydes and ketones are readily reduced by LAH into corresponding alcohols.  Sodium borohydride reacts slowly with water and usually reactions are carried out in at room temperature. Being less reactive than lithium aluminium hydride, it is more selective in its action. It reduces aldehydes and ketones to the corresponding alcohols but alkenes, alkynes, Esters, , lactones, carboxylic acids, nitro, and nitriles are not reduced.

CHEMISTRY Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module 16: Reduction by Metal hydrides – Part-I