Reduction of Amides

When a carbonyl group is linked to a nitrogen atom and thus forming a functional group which is known as an amide, as is any chemical with the amide functional group. Amides are formed by combining a carboxylic acid to amine. The inorganic anion NH2 is also known as amide. It’s ammonia’s conjugate base (NH3). The basis on which amine groups classify, if the amine group has the form of NH2, NHR, or NRR’, where R and R’ are non-hydrogen groups then they refer as primary, secondary, and tertiary amines respectively. In both nature and technology amides can be found. Proteins and polymers like Nylons, Twaron, and Kevlar are polymers with amide groups (polyamides) connecting their units; these formations are produced easily , and thus they provide structural exactingness, and resist hydrolysis. They possess many additional significant biological molecules, as well as medications such as paracetamol, penicillin, and LSD, which are amides. Solvents having a low molecular weight, such as dimethylformamide, are commonly used. 

Amides and its properties

• Bonding 

Nitrogen having a lone pair of electrons is then delocalized by the carbonyl group and thus result in the formation of a partial double bond between nitrogen and carbon. In actuality, delocalized electrons occupy molecular orbitals in the O, C, and N atoms, and thus form a conjugated system. As a result, the three nitrogen bonds in amides are planar in nature rather than pyramidal (as in amines). Because of this planar limitation, it inhibits rotations around the N linkage, which has significant implications for the mechanical properties of bulk material in such molecules and also for the configurational properties of macromolecules formed by such connections. Because of their inability to spin, amide groups are distinguished from ester groups, resulting in a more flexible bulk material.

• Solubility 

Amide and ester solubilities are essentially equivalent. Because these molecules may both donate and accept hydrogen bonds, carboxylic acid and amines are more soluble than amides. Excluding N,N-dimethylformamide, tertiary amides have a low water solubility.

• Basicity 

Amides are also one of the examples of weak bases as contrasted to amines. The pKa value of Conjugate acid of amine is 9.5, whereas the pKa value of a conjugate acid of amide is 0.5. As a result, amides don’t have as obvious acid–base characteristics in water. The carbonyl withdraws electrons first from amine, which explains the relative lack of basicity.

Reduction of Amides

• Catalytic reduction of amides

The catalytic hydrogenation of amides is of tremendous interest to organic chemists since the amines produced are widely used in natural products, medicines, agrochemicals, dyes, and other items. Direct hydrogenation of amides using molecular hydrogen is a greener approach than typical reduction of amides using (over)stoichiometric reductants. Furthermore, it is a highly versatile transformation since it can selectively access not only higher amines (obtained by C–O cleavage), but also lower amines and alcohols, or amino alcohols (obtained by C–N cleavage). 

To convert amides to amines, catalytic hydrogenation can be utilised; however, the procedure frequently necessitates high hydrogenation pressures and reaction temperatures. Selective catalysts for reactions are copper chromite, Rhenium trioxide, and Rhenium(VII) oxide etc.

• Non- catalytic reduction of amides

Metal hydrides such as lithium aluminium hydride or lithium borohydride in solvent systems like tetrahydrofuran and methanol are reducing agents that can alter this process.

• Reduction of amide to amines

First step, The electrophilic C in the polar carbonyl group of the ester reacts with the nucleophilic H form of the hydride reagent. Electrons from the C=O migrate to the electron – deficient O, forming a metal alkoxide intermediary complex.

Second step, as part of a metal alkoxide leaving group, the tetrahedral intermediate collapses and displaces the O, resulting in a highly reactive iminium ion as an intermediate.

Third and the last one, as it contributes to the electrophilic C in the iminium system, the nucleophilic H from the hydride reagent undergoes rapid reduction. The amine product is formed when electrons from the C=N travel to the cationic N, neutralising the charge.

• Reduction of amide to aldehydes

To convert a variety of amides to their corresponding aldehydes under relatively moderate reaction conditions and in high yields Schwartz’s reagent has been used. With extraordinary chemoselectivity, a variety of 30 amides, including Weinreb’s amide, can be converted directly to the same aldehydes. 10 and 20 amides were also shown to be viable reduction substrates, however yields were lower than those of the corresponding tertiary amides.

In general, reducing amides to aldehydes using commonly accessible metal hydrides generates aldehydes in low to moderate yields, with the corresponding alcohols and amines isolated as by-products in many circumstances.

The reaction of tertiary amides with lithium aluminium hydride yielded a combination of the matching amine and the alcohol, according to early research.

After that, it was discovered that adding the reagents in reverse order (adding the hydride to the amide) resulted in the creation of a considerable number of the corresponding aldehydes.

It was also discovered that increasing the size of the substituents at the amide nitrogen resulted in a larger aldehyde yield.

Conclusion

In the synthesis of peptides and proteins from amino acid monomers, amides are essential components, hence they play an important role in life chemistry. They are produced in multi million ton quantities in factories, they are also found in synthetic polymers such as nylon. As a result, organic chemists have devised a plethora of techniques for their synthesis throughout the last century. Their widespread use stems from their chemical structure, which makes them the most stable carboxylic acid derivatives since towards nucleophilic reactions they are least reactive on the carbonyl group. The difference in electrical nature of nitrogen and oxygen in amides’ structure is primarily responsible for their inertness.