Amines, amides, amino acids and proteins (Topic 18B)

Amides are functional groups also based on amines, with a hydrogen atom substituted for an acyl group, .

A primary amide has the general formula , with the nitrogen only bonded to one carbon atom, retaining two hydrogen atoms.

The acyl group in an amide can originate from acyl chlorides, acid anhydrides, or carboxylic acids.

A secondary amide has the structure .

In a secondary amide the nitrogen is bonded to two carbon atoms and only one hydrogen.

Secondary amines and amides are easily confused.

In a secondary amine, two alkyl carbon R groups are bonded to the with a single remaining hydrogen. The lone pair in an amine is basic.

In a secondary amide, a carbonyl group will always bond directly to the nitrogen atom. The amide group is susceptible to hydrolysis, and the nitrogen’s lone pair is not basic.

Amino acids are organic compounds that contain both an amine group () at one end and a carboxylic acid group ) at the other end.

In addition to these functional groups, amino acids have the following structural features:

1. Central carbon atom (-Carbon)

The amine group and carboxylic acid group are bonded to the same central carbon atom, called the -carbon.

2. R group

Each amino acid has a unique side chain, or R group, attached to the -carbon. The R group determines the specific properties and identity of the amino acid.

Hydrogen atom

The -carbon is also bonded to a single hydrogen atom.

Aliphatic amines are more basic than aromatic amines.

Aliphatic amines are more basic due to electron donation from alkyl groups, which increases the lone pair’s availability for protonation.

Aromatic amines are less basic because electron withdrawal through conjugation with the benzene ring reduces the availability of the nitrogen’s lone pair.

The relative base strength of aliphatic amines depends on how easily the nitrogen lone pair can be donated.

groups are electron donating towards the nitrogen, and facilitate accessibility of the lone pair.

Tertiary amines are stronger bases than secondary amines, which are stronger bases than primary amines, due to the decreasing number of groups.

It is worth noting that recent work has disproved the ‘inductive nature’ of groups but the terminology is still used in many resources and exams. In reality the electron donation is caused by a combination of polarisability and hyperconjugation; in terms of electronegativity the groups are actually inductively withdrawing!

Primary amines, react with acyl chlorides in a nucleophilic addition elimination reaction to form a N-substituted amide and hydrochloric acid.

Step 1: Nucleophilic addition
The nitrogen atom of the amine has a lone pair of electrons, making it a nucleophile.

The lone pair on the nitrogen attacks the electrophilic carbon atom of the carbonyl group () in ethanoyl chloride. This weakens the π-bond in the bond, causing it to break and form a tetrahedral intermediate.

Step 2: Elimination
The lone pair on the oxygen reforms the double bond, expelling the chloride ion () as the leaving group.

Step 3: Proton transfer
The expelled chloride ion acts as a base and attacks the hydrogen atom attached to the positive nitrogen. This removes the positive charge from the nitrogen to form the N-substituted amide.

Note that the formed reacts with any unreacted amine in the mixture to form an alkyl ammonium chloride.

The nucleophilic substitution reaction mechanism for the formation of primary amines from haloalkanes is shown below:

The carbon atom, of the polarised carbon-halogen bond of a haloalkane, is readily attacked by the nucleophilic nitrogen’s lone pair.

In the reaction, the initial nucleophilic attack is followed by deprotonation by a second ammonia molecule. In this case the ammonia acts as a base.

The halide ion is lost as an ammonium salt, and the substituted amine product is formed.

The mechanism for formation of a secondary or tertiary amine is primarily the same, but features an amine nucleophile.

Amines can be produced by the reduction of nitriles, , by hydrogenation.

is used as a reducing agent, under acidic conditions to reduce the nitrile to an amine.

can be used to represent a reducing agent. Four equivalents of are required to reduce a nitrile group.

Nitriles can also be reduced to primary amines through catalytic hydrogenation using a catalyst with hydrogen.

Aromatic primary amines have the amino group directly bonded to a carbon atom in the benzene ring.

They are prepared by a reduction of the corresponding aromatic nitro compound.

The reaction is carried out by refluxing with metallic tin, , and concentrated hydrochloric acid.

The initial product formed is a salt, due to the strongly acidic conditions, so treatment of the product with is required to liberate the aromatic amine.

It is conventional to represent the reducing reagents as and are needed to reduce each aromatic group to .

Condensation polymerisation occurs when many monomers combine with the elimination of a small molecule, such as , or .

where = a whole number.

Condensation polymerisation can occur with one monomer or a pair of monomers.

The two classes of polymer formed by condensation polymerisation are polyesters and polyamides.

Polyamides have the secondary amide group when the two functional groups react together.

Dicarboxylic acid monomers react with diamine monomers via condensation polymerisation, forming polyamides and water.

The dicarboxylic acid and the diamine have functional groups at both ends, so each monomer can form two amide links.

There is an amide group within the repeat unit, and two water molecules are produced per repeat unit formed.

If a polyester is made from two different monomers, a dicarboxylic acid (or diacyl chloride) and a diol, the order of the ester connectivity will alternate across the polymer and both monomers must appear in the repeating unit.

To draw the repeat unit:

• Draw the ester group in the middle of the structure.
• Add the dicarboxylic acid (or diacyl chloride) carbon skeleton to the left of the group, and terminate the left side with the last group, a trailing bond, and a repeat unit bracket.
• Draw the diol carbon skeleton on the right of the central from the ester and terminate on the right with the group, a trailing bond, and a repeat unit bracket.

If a polyamide is made from two different monomers, the order of the amide connectivity will alternate across the polymer and both monomers must appear in the repeating unit.

• Draw the secondary amide group in the middle of the structure.
• Add the dicarboxylic acid (or diacyl chloride) carbon skeleton to the left of the group, and terminate on the left with the group, a trailing bond, and a repeat unit bracket.
• Draw the diamine carbon skeleton to the right of the central from the amide group, and terminate on the right with the group, a trailing bond, and a repeat unit bracket.

When amino acids join together they form polyamides. As there is a single monomer, the amide group will not be seen in the repeat unit and the order of connectivity of the amide group remains the same along the chain.

Polyamides can be formed from a single monomer with both the carboxylic acid and the amine group on the same carbon skeleton.

These monomers are known as amino acids.

During polymerisation, amino acids link together to form a type of polyamide called a polypeptide through condensation reactions.

All polypeptides are polyamides but not all polyamides are polypeptides.

Be cautious when reactions involve amino acids; they can contain additional functional groups which will impact their reactivity.

Amino acids have both an amino and carboxylic acid group.

Amino groups are Brønsted–Lowry bases; they accept protons to form ions.

Carboxylic acids are Brønsted–Lowry acids, and donate protons to form ions.

Amino acids that are used in protein formation are known as alpha () amino acids, or 2-amino acids.

The carbon after the carboxylic acid group carbon, (carbon 2), is the carbon and also holds the amino group, a hydrogen atom and the variable group, .

At values close to seven, the amino acid contains both a group and group.

A molecule that contains both positive and negative ions, whilst remaining neutral overall, is called a zwitterion.

As they contain both positive and negative ions, the zwitterions can form a giant ionic lattice; therefore, pure amino acids form crystalline solids.

In acidic conditions, the basic part of the amino acid is protonated.

The amino group is basic and the lone pair of electrons on the amino nitrogen can be donated to a proton in a dative covalent bond. The product is an ammonium salt made charge neutral by the anion from the acid used.

Note that the carboxylic acid group also remains protonated in acidic conditions.

In alkaline conditions, there is a high concentration of ions, and so the acidic part of the amino acid is deprotonated.

The carboxylic acid group acts as a Brønsted–Lowry acid, and donates a ion to the solution. The products are a carboxylate salt with the cation from the base, and water: a neutralisation reaction.

Note that the amine group remains deprotonated and uncharged in alkaline conditions.

Most 2-amino acids (apart from glycine) contain a chiral carbon atom, with the -carbon atom bonded to four different atoms or groups.
Chiral molecules exist as two enantiomers, which are non- superimposable mirror images of each other.

When formed in living organisms these are enantiomerically pure. In abiotic synthesis they are formed as a racemic mixture.

When plane-polarised monochromatic light is passed through aqueous solutions of amino acids the plane of polarisation rotates clockwise for one enantiomer and anticlockwise for the other. An observed rotation indicates that one enantiomer is in excess. No rotation indicates a racemic mixture.

Proteins are formed from chains of amino acids which join together through peptide bonds.

When a peptide bond is formed, water is eliminated in a condensation reaction.

Proteins can be broken down into their constituent amino acids in a hydrolysis reaction (hydro meaning water, and lysis, meaning to split).

In this reaction, water is inserted into the peptide bond, splitting the chain to reform amino acids.

A hydrolysis reaction usually takes place in the presence of an acid catalyst (e.g. concentrated )

The from the water molecule is added back onto the carbonyl carbon to reform the carboxylic acid.

The from the water molecule is added onto the nitrogen to reform the amine.

When amino acids form peptides, a condensation reaction occurs, and water is eliminated.

The is removed from the carboxylic acid group, and the is lost from the amine group on the neighbouring amino acid.

A peptide bond, , is then formed between the fragments of the amino acids left over.

For colourless amino acids to be visible on a TLC plate – and hence their value be calculated – UV light or ninhydrin may be used.

Ninhydrin is a reagent which will bind to the amine group generating a blue or purple coloured complex.