Paper 9: ORGANIC CHEMISTRY-III (Reaction Mechanism-2) Module17: Reduction by Metal hydrides Part-II CHEMISTRY

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1 Subject Chemistry Paper No and Title Module No and Title Module Tag 9: ORGANIC -III (Reaction Mechanism-2) 17: Reduction by Metal hydrides Part-1I CHE_P9_M17

2 Table of Contents 1. Learning Outcomes 2. Introduction 3. Reduction of unsaturated carbonyl compounds 3.1 Relook on conjugation 3.2 Reduction with NaBH4 3.3 Reduction with DIBAL-H: 4. Reduction of carboxylic acids 4.1 Reductions of carboxylic acids to alcohols 4.2 Reductions of carboxylic acids to aldehydes 5. Reduction of Carboxylic acids derivatives 5.1 Reduction of carboxylic Esters to alcohols 5.2 Conversion of carboxylic acid derivatives to aldehydes 5.3 Reduction of acid amides to amines 6. Reduction of unsaturated carboxylic acids and esters 7. The reduction of Nitriles 7.1 Reduction of Nitriles to Amines 7.2 Reduction of Nitriles to Aldehydes 8. Reduction of unsaturated nitriles 9. Summary

3 1. Learning Outcomes After studying this module, you shall be able to Understand the hydride reduction on conjugated carbonyl compounds Comprehend the hydride reduction of carboxylic acids and derivatives Understand the hydride reduction of nitriles and unsaturated nitriles Apply the reduction using different hydrides on combinations of functional groups present in same compound. 2. Introduction Reduction is an invaluable process and can be used to remove functionality from a molecule and also for introducing stereocenters. In the previous module, we have studied that the reduction of carbonyl compounds to alcohols by metal hydrides involves the nucleophilic addition of hydride ion to the carbonyl group. The most common metal hydrides are lithium aluminium hydride (LiAlH4) and sodium borohydride (NaBH4). Unsaturation brings more chemistry to life. Conjugated double bonds have different properties from isolated double bonds, both physically and chemically. What will happen if there is unsaturation in the molecules bearing the carbon-hetero atom multiple bond? Will the reduction happen similarly or take some different course? In this module, we shall continue the study of reduction by hydrides on other groups like carboxylic acids and derivatives and nitriles and also see how the presence of conjugated double bonds affect the reduction. 3. Reduction of Unsaturated carbonyl compounds 3.1 Relook on conjugation You are already aware that the stability of conjugated dienes is higher than the nonconjugated dienes due to delocalization of charge through resonance. Let us understand how the presence of conjugation changes the reactivity of carbonyl compounds towards reduction by metal hydrides.

4 A carbonyl group shows nucleophilic addition reactions at carbonyl carbon. But look at the following examples A and B, they are the products of addition, not to the carbonyl group, but to the C=C bond. This is known as conjugate addition. Conjugate addition or direct addition to the carbonyl group? When do nucleophiles undergo conjugate addition (also called 1,4-addition ) and when do they add directly to the carbonyl group ( 1,2-addition )? This depends on the following factors: conditions of the reaction nature of the α,β-unsaturated carbonyl compound type of the nucleophile Reduction of α,β-unsaturated carbonyl derivatives poses a potential problem due to possibilities of 1,2 as well as 1,4 addition. Reduction with LiAlH4: Reduction of benzalacetone (10) can lead to either the allylic alcohol (11) via normal 1,2-addition of hydride to the carbonyl, or to the saturated alcohol (12) via 1,4-reduction (delivery of hydride to the alkenyl carbon). 3.2 Reduction with NaBH4: Sodium borohydride reduces α,β -unsaturated aldehydes and ketones to saturated alcohols.

5 The borohydride has reduced not only the carbonyl group but the double bond as well. In fact, the double bond is reduced first in a conjugate addition, followed by addition to the carbonyl group. 3.3 Reduction with DIBAL-H: Conjugated carbonyl compounds are reduced to allylic alcohols in the presence of diisobutylaluminum hydride (DIBAL-H) or sodium borohydride and cerium chloride. 4. Reduction of carboxylic Acids 4.1 Reduction of Carboxylic Acids to alcohols Carboxylic acids are easily reduced to primary alcohols by LiAlH4. The reaction goes via the intermediate stage of aldehyde, but does not stop at the aldehyde stage. The conditions required are particularly mild and the reduction proceeds quite well at normal temperature.

6 Example: NaBH4 and catalytic hydrogenation (i.e.h2/pt or H2/Ni) are ineffective for the reduction of carboxylic acid. The NaBH4 being a weak nucleophilic reagent, cannot attack the carbon of carboxylic groups as compared to the carbonyl group. Other hydrides have also been used to reduce carboxylic acid to alcohol: A combination of NaBH4 and an arylboronic acid have been used. E.g., Benzyltriethylammoniumborohydride in dichloromethane converts carboxylic acids to the alcohol. Borane is mainly good for carboxyl groups and allows selective reduction of carboxylic group in the presence of other groups (the reaction with double bonds takes place at about the same rate in ether solvents). Borane also reduces carboxylic acid salts. 4.2 Reduction of Carboxylic Acids to aldehydes Reduction of carboxylic acids to aldehyde stage is difficult because aldehydes are more reactive than carboxylic acids towards most reducing agents. Almost any reagent which converts acids to aldehydes also reduces aldehydes to primary alcohols. This can be achieved if we take weak reducing agent, e.g., lithium aluminium-tri(tbutoxy)hydride ( LiAl[OC(CH3)3]3H). It is weaker reducing agent as compared to lithium aluminium hydride. Acid chlorides are strong activators for the nucleophilic addition (due to I effect of Cl). Hence, it converts acid chlorides to aldehydes without further

7 reduction to alcohol. In these conditions, the aldehyde reduces more slowly and can be easily isolated. Mechanism Acid reduction to an aldehyde is a two-step process. Let us understand this with the help of following example: The first step is the conversion of the acid to the acid chloride The second step is the reduction of acid chloride using lithium aluminium-tri(tbutoxy)hydride into the corresponding aldehyde. 5. Reduction of carboxylic acid derivatives LiAlH4 reduces all type of carbonyl groups viz., in aldehyde, ketones, esters, carboxylic acids and amides. Each of these reductions gives an alcohol as the product, except the reduction of amide with LiAlH4, which gives an amine. The decreasing order of reactivity is as follows:

8 Note that the carboxylic acid and acid derivatives are not reduced by NaBH4. This is because the acid and acid derivatives are less electron deficient at the electrophilic carbon due to electron donating +M effect of the OR or NR2 or OH groups. 5.1 Reduction of Carboxylic Esters to Alcohols Lithium aluminum hydride reduces carboxylic esters to give two equivalents of alcohol. The reaction is of wide scope and has been used to reduce many esters. For example, Lactones yield diols. Among the reagents lithium triethylborohydride, LiAlH(Ot-Bu)3, and BH3-SMe2 in refluxing THF give the same product. Phenolic esters containing electron-withdrawing groups are reduced by NaBH4, but the reaction with other esters is slow therefore NaBH4 cannot be used as reagent for such reactions. Carboxylic esters can also be reduced to alcohols by hydrogenation over copper chromite catalysts, although high pressures and temperatures are required. Ester functions generally survive low-pressure catalytic hydrogenations. Before the LiAlH4 was discovered as the reducing agent for esters, the reaction was done using sodium in ethanol, a method known as the Bouveault Blanc procedure. This procedure is still sometimes used where selectivity is necessary.

9 5.2 Conversion of carboxylic acid derivatives to aldehydes There are few methods for reduction of carboxylic acid derivatives to form aldehydes; these methods are useful to change the properties of LAH such as reactivity and stability to allow partial reductions. For example, alkoxy or alkyl groups can be attached to aluminum in order to modifies the reactivity of the reagent as a hydride donor and also increases its solubility in nonpolar solvents. Two such reagents are Lithium tri-tertbutoxyaluminohydride (LtBAH), LiAl[OC(CH3)3]3H : Soluble in THF, diglyme & ether; Diisobutylaluminum hydride (DIBAH), [(CH3)2CHCH2]2AlH : Soluble in organic solvents such as toluene, THF & ether. Each of them has one equivalent of hydride only. Of these, Di-isobutyl aluminium hydride (i-bu2alh)2 (DIBAL-H or DIBAL ) is most commonly used for reducing carboxylic acid esters to aldehydes. This on the contrary, cannot be done using lithium aluminumhydride which give rise to alcohols. This is because, DIBAL is a weaker reducing agent and hence the reaction stops at aldehyde stage and no further reduction to alcohol take place. Example: Another example: Examples of reduction of acid chloride and acid amides to aldehydes:

10 5.3 Reduction of acid amides to Amines Acid amides do not give alcohols on hydride reduction, in contrast to other acid derivatives. Reaction of an amide with LiAlH4 initially gives an intermediate iminium salt, which is further reduced to an amine as the final product. Oxygen is completely removed from the molecule. For example, 6. Reduction of unsaturated Carboxylic Acids and esters For unsaturated esters, conjugate addition occurs. There is also a significant role of steric hindrance. If the β carbon of a carbonyl compound is more hindered, the nucleophile is less likely to attack there. But there are a number of nucleophiles that can undergo conjugate addition even at such highly substituted carbon atoms.. When lithium aluminium hydride is used as the source of H to attack as nucleophile on esters, the esters get reduced to alcohols. The reduction of α, β-unsaturated esters with DIBAL in polar solvents result in formation of allylic alcohols. E.g.,

11 7. The Reduction of Nitriles 7.1 Reduction of Nitriles to Amines LiAlH4 is a very strong reducing agent and is used to reduce nitrile. In the case of nitriles, the carbon of the carbon nitrogen triple bond acts as electrophilic center where the hydride is attached because the nitrogen being electronegative, the carbon is made electron deficient. Here, the hydride adds twice to the nitrile due to the triple bond. During the reaction, the aluminum complex basically acts as a giant proton i.e. a Lewis acid.

12 7.2 Reduction of Nitriles to aldehydes Diisobutylaluminium Hydride (DIBAL-H or DIBAL) can be used to reduce only one "oxidation state" i.e., from carbon nitrogen triple bond (-CN) to carbon-nitrogen double bond (-CH=N-). The later on hydrolysis leads to aldehyde formation. Hence DIBAL reduces nitriles to aldehydes. Notice that The mechanism for this is different because it is a Lewis acid. Hence it is required to coordinate with a Lewis base first before activating, followed by which the hydride is intramolecularly delivered. Unlike the other metal hydrides it is an electrophilic reagent. Another example: 8. Reduction of unsaturated nitriles Lithium aluminum hydride reduces nitriles to primary amines without affecting the alkene double bond in the unsaturated or conjugated nitriles. E.g.,

13 (I) (II) (III) (IV) Here, electrophilic nitrile carbon in (I) when attacked by hydride generates intermediate salt of an imine (II). Subsequently, the second hydride attacks the carbon via shift from aluminium to form metal amine salt (III). This metal amine salt on hydrolysis produces primary amine (IV). In reduction of carboxylic acid derivatives, sodium borohydride reacts with acyl chlorides and anhydrides in the presence of hydroxylic solvents such as water and alcohols. But at low temperatures they are sparingly soluble in nonpolar solvents. Also, sodium borohydride (NaBH4) is less reactive than LiAlH4, it cannot reduce amides and acids and slowly reduces esters. 9. Comparison Comparison of efficiency of various reducing agents to reduce the different functional groups

14 10. Summary LiAlH4 is a versatile reducing agent and reduces carbonyl compounds such as aldehydes and ketones, carboxylic acids, acid chlorides, acid anhydrides, esters, amides and nitriles. Reduction of α,β-unsaturated carbonyl derivatives poses a potential problem due to possibilities of 1,2 as well as 1,4 addition. Reduction of carboxylic acids and derivatives to alcohols can be achieved very easily by using LiAlH4, but for stopping at aldehyde stage other milder hydride reagent like DIBAL-H is used. Amides and nitriles on reduction with LiAlH4 produce amines.