20.7 Chemistry of Nitriles

Structure and Reactivity of Nitriles

Nitriles contain a carbon-nitrogen triple bond ($-C\equiv N$), and their chemistry revolves around the electrophilic character of that carbon. Understanding how this functional group behaves opens up several useful synthetic pathways, from building carboxylic acids to making amines and ketones.

The nitrile carbon is sp-hybridized, which gives the group a linear geometry. Because nitrogen is more electronegative than carbon, it pulls electron density away from the carbon through the triple bond. This creates a significant partial positive charge ($\delta^+$) on the carbon, making it a good target for nucleophilic attack.

Compared to carboxylic acids ($RCOOH$):

• Nitriles are less polar because they lack both the acidic $OH$ hydrogen and the carbonyl oxygen, which limits their hydrogen bonding ability.
• Nitriles are weaker acids. A carboxylate anion ($RCOO^-$) is stabilized by resonance across two equivalent oxygen atoms, while the conjugate base of a nitrile doesn't have that same stabilization.
• Nitriles are actually more electrophilic at the carbon atom than carboxylic acids. The nitrogen's electron-withdrawing effect through the triple bond concentrates positive character on that carbon, making nucleophilic addition more favorable.

Electronic Properties of Nitriles

You can draw two key resonance structures for a nitrile:

• $R-C\equiv N$ (triple bond, no formal charges)
• $R-\overset{+}{C}=\overset{-}{N}$ (double bond, with formal charges on C and N)

The second contributor places a full positive charge on carbon and a negative charge on nitrogen. While the triple-bond structure dominates, the charge-separated form helps explain why the nitrile carbon is so electrophilic and why nucleophiles readily attack it.

The sp hybridization also matters practically: the linear geometry means there's no steric crowding around the electrophilic carbon from the nitrile group itself, so incoming nucleophiles have relatively easy access.

Methods for Nitrile Synthesis

$S_N2$ Reaction with Cyanide

The most straightforward way to make a nitrile is to react an alkyl halide with cyanide ion ($CN^-$).

1. Cyanide acts as the nucleophile, attacking the carbon bearing the halide leaving group.
2. The halide ($X^-$) departs in a classic $S_N2$ mechanism.
3. Stereochemistry inverts at the carbon center due to backside attack.

$CH_3CH_2Br + NaCN \rightarrow CH_3CH_2CN + NaBr$

This works best with primary and methyl halides. Secondary halides tend to give elimination products, and tertiary halides won't undergo $S_N2$ at all. Also note that this reaction adds one carbon to the chain, which makes it a useful chain-extension tool.

Dehydration of Amides

Primary amides ($RCONH_2$) can be converted to nitriles by removing water with a dehydrating agent, typically phosphorus oxychloride ($POCl_3$) or thionyl chloride ($SOCl_2$).

1. The dehydrating agent reacts with the amide to form a reactive imidoyl chloride intermediate ($RCCl=NH$).
2. Elimination of $HCl$ from this intermediate gives the nitrile.

$CH_3CONH_2 \overset{POCl_3}{\longrightarrow} CH_3CN + H_2O$

This is especially useful when you already have the amide in hand and need to convert it to the nitrile without changing the carbon skeleton.

Key Reactions of Nitriles

Hydrolysis to Carboxylic Acids

Nitriles can be hydrolyzed all the way to carboxylic acids. This is a two-stage process, though you don't always isolate the intermediate.

1. Water (or hydroxide) attacks the electrophilic nitrile carbon.
2. The initial addition product tautomerizes to an amide ($RCONH_2$).
3. The amide then undergoes further hydrolysis to yield the carboxylic acid ($RCOOH$) and ammonia (or ammonium ion under acidic conditions).

$CH_3CN + 2H_2O \overset{H^+/OH^-}{\longrightarrow} CH_3COOH + NH_3$

This reaction works under either acidic or basic conditions. If you want to stop at the amide stage, you can use milder conditions or controlled reaction times, though full hydrolysis is more common in practice.

Reduction to Primary Amines

Reducing a nitrile gives a primary amine with one more carbon than the original chain (if you started from an $S_N2$ synthesis). Two common reducing methods:

• $LiAlH_4$ (strong hydride reducing agent, followed by aqueous workup)
• Catalytic hydrogenation ($H_2$ with a metal catalyst such as Pd, Pt, or Raney Ni)

$CH_3CN \overset{LiAlH_4}{\longrightarrow} CH_3CH_2NH_2$

The reduction passes through an imine intermediate ($RCH=NH$), which is further reduced to the amine. With $LiAlH_4$, both reductions happen in the same pot. The product is always a primary amine, which is a distinct advantage since primary amines can be hard to make selectively by other routes.

Grignard Addition to Form Ketones

Grignard reagents ($RMgX$) add to the electrophilic nitrile carbon, and after acidic hydrolysis, you get a ketone.

1. The Grignard reagent attacks the nitrile carbon, forming a metalated imine intermediate ($R_2C=NMgX$).
2. Acidic aqueous workup ($H_3O^+$) hydrolyzes the imine to a ketone.

$CH_3CN + CH_3MgBr \rightarrow (CH_3)_2C=NMgX \overset{H_3O^+}{\longrightarrow} (CH_3)_2C=O$

This is a useful way to build ketones because you're forming a new carbon-carbon bond in the process. The imine intermediate doesn't react with a second equivalent of Grignard reagent (unlike esters or acid chlorides), so you get clean monoaddition. That's a real synthetic advantage when you need a ketone specifically.