Amines, amides and amino acids
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Amines are organic derivatives of ammonia.
They have groups, (alkyl or aryl), substituted in place of ammonia hydrogens.
Amines, like ammonia, act as bases by donating the lone pair on the nitrogen atom in a dative covalent bond to protons.
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.
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, .
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.
Amines and ammonia react with inorganic acids, such as , in an acid–base reaction.
The nitrogen atom acts as a base, using its lone pair to form a dative covalent bond to the proton.
The product is a neutral ammonium or alkylammonium salt following reaction with ammonia or an amine.
Aliphatic amines are more basic than aromatic amines.
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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 hydrochloric acid to form alkylammonium chloride.
The primary amine ethylamine () reacts with hydrochloric acid to form the salt ethylammonium chloride.
Secondary amines react with hydrochloric acid to form dialkylammonium chloride.
The secondary amine diethylamine will similarly react with forming the salt diethylammonium sulfate.
Note that charge balancing is required to form a charge-neutral salt.
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.
Primary amines can be formed from haloalkanes refluxed with excess ethanolic ammonia. Ethanolic solvent is used to prevent hydrolysis of the haloalkane.
For a good yield of primary amines, must be in excess.
Secondary amines and tertiary amines can also be formed.
The amine products act as nucleophiles, and compete with the ammonia in subsequent substitutions. Further substitutions are less likely to occur if the ammonia is in excess, so there are many fewer R groups available for subsitiution and a higher concentration of the nucleophile.
Secondary amines can be formed as a major product in the nucleophilic substitution reaction between haloalkanes and excess ethanolic primary amine.
Ethanolic solvent is used to prevent hydrolysis of the haloalkane.
The carbon atom, of the polarised carbon-halogen bond, is readily attacked by nucleophiles, such as ammonia and amines.
To ensure the secondary amine is the major product the primary amine must be in excess.
Tertiary amines can be formed as a major product in the nucleophilic substitution reaction between haloalkanes and an excess secondary amine.
where is a halogen.
The reaction occurs in ethanolic conditions.
Ammonia and amines act as nucleophiles, substituting the halogen atom in haloalkanes.
If the haloalkane is in excess, a mixture of primary, secondary, and tertiary amine products will be formed.
Primary amines react with acid anhydrides in a nucleophilic addition–elimination reaction to form an N-substituted amide and carboxylic acids.
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 acid anhydride. This weakens the -bond in the bond, causing it to break and form a tetrahedral intermediate.
Step 2: Deprotonation
The amide nitrogen is positively charged due to the addition of the hydrogen during nucleophilic attack.
A proton transfer occurs where the positively charged nitrogen loses a hydrogen ion () to another molecule of amine.
Step 3: Elimination
The lone pair on the oxygen reforms the double bond, expelling the carboxylate ion as the leaving group.
This step converts the intermediate into the N-substituted amide product and the carboxylate ion.
The carboxylate ion can react with to form a carboxylic acid.
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 .
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.
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.
The carboxylic acid group of an amino acid, can undergo a condensation reaction with an alcohol in the presence of a strong acid catalyst, such as sulfuric acid, to form an ester and water.
The reaction is reversible and slow.
Although the conditions remain acidic, the amine group will be protonated.
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.
The peptide bonds between amino acids in the protein chain are strong covalent bonds, and are not easily broken. This chain of amino acids provides the primary structure of the protein.
The secondary and tertiary structures of the protein are formed by hydrogen bonds. These are much weaker than covalent bonds, and can be broken when heated.
In the tertiary structure, sulfur–sulfur bonds can also form between cysteine amino acids, as they contain sulfur in their group.
Sulfur–sulfur bonds or disulfide bridges are a type of covalent bond, and are therefore stronger than hydrogen bonds. Disulfide bridges make the protein shape more resistant to changes in heat and .
The sequence in which amino acids bond together is a protein’s primary structure. The primary structure is held together by peptide bonds, which are strong covalent bonds and not easily broken.
The secondary structure is the local 3D arrangement of the protein: it will either be an -helix or a -pleated sheet.
The secondary structure is held together by hydrogen bonds between nearby amino acids. These are usually represented as dashed lines between nearby amino acids.
The tertiary structure refers to the 3D shape of the entire protein.
The tertiary structure is formed through hydrogen bonds and sulfur–sulfur bridges between the R-groups on amino acids throughout the structure.
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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 )
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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.
Amino acids can be separated and identified using thin layer chromatography (TLC).
Each amino acid will have a different affinity to the mobile phase (solvent) and the stationary phase (the TLC plate). A combination of these interactions dictates how far up the TLC plate each component will travel.
The value quantifies this effect and is calculated as:
Amino acids can be identified by comparing the value in a given solvent to a database value.
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.
The value is calculated as:
When measuring the distance travelled by the amino acids, you should measure from the centre of the spot on the TLC plate.
Measurements should be made following the direction of travel shown by the solute. This will be from the start point through the spots left by the sample.
Enzymes are an important example of proteins. They are biological catalysts and speed up the rate of metabolic processes.
Enzymes have an active site which binds to the substrate the enzyme acts upon. Once in an enzyme–substrate complex, the activation energy for the process is reduced and the reaction progresses.
Stereoisomers have different spatial arrangements. As a result, one stereoisomer will be complementarily shaped to the active site, whereas another may not. This makes the active site stereospecific.
Enantiomers are stereoisomers which are mirror images. The wrong enantiomer will not fit the enzyme’s active site, in the same way that you cannot comfortably put your right shoe on your left foot; their shapes are not complementary.
The 3D shape of the active site is a feature of the tertiary structure of the protein, and is held together by hydrogen bonds and disulfide bridges bonds.
If hydrogen bonds or disulfide bridges are broken by high temperatures or extremes of the tertiary structure is disrupted and the shape of the active site will change. This stops the enzyme–substrate complex from forming; the enzyme is denatured and no longer effective.
If the active site is blocked in any way, the substrate can no longer bind to the enzyme, rendering the enzyme inactive.
Scientists can exploit this, by designing inhibitor drugs, which bind to the active site of an enzyme in a bacteria or virus, in place of the substrate, slowing down its action.
Drugs that bind to the enzyme active site are called competitive inhibitors.
Some poisons, such as snake venom, are competitive inhibitors.
These work by mimicking the shape of the intended substrate, inhibiting enzymes in the body which catalyse important metabolic processes.
Enzyme structure is extremely complex. Designing a drug to fit the active site of an enzyme is aided by high power computers.
Computers can model intramolecular forces, predicting the 3D structure of the protein, including the active site.
The models can determine how different drug structures would interact with the enzyme, including how well it would bind with and block the active site. This provides target molecules for lab synthesis.