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F324 Amino Acids & Chirality

Amino acids

ContextAmino acids are the building blocks for biological molecules called peptides, and for proteins (polypeptides). The body has 20 different amino acids from which to assemble proteins.

Proteins act as enzymes, hormones, antibodies, and transport substances such as oxygen, vitamins and minerals to cells throughout the body. They are involved in the formation of bones, teeth, hair, skin, blood vessels and other tissues

StructureAn amino acid contains the functional groups –NH2 and –COOH (amine and carboxylic acid).

In an -amino acid (such as the 20 the body uses to make proteins) the –NH2 and –COOH groups are both bonded to the same carbon atom, along with a –H atom.

The general formula of an -amino acid can therefore be written as:

or RCH(NH2)COOH

The R-group is usually an alkyl group but can contain –OH, -SH, -COOH or –NH2 groups.

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Amino Acids state the general formula for an α-amino acid as RCH(NH2)COOH state that an amino acid exists as a zwitterion at a pH value called the isoelectric point state that different R groups in α-amino acids may result in different isoelectric points describe the acid–base properties of α-amino acids at different pH values

Isoelectric points will be provided in the exam paper

Peptide formation and hydrolysis of proteins explain the formation of a peptide (amide) linkage between α-amino acids by condensation

and subsequent condensation polymerisation to form polypeptides and proteins describe the acid and the alkaline hydrolysis of proteins and peptides to form α-amino acids

or carboxylates

Optical Isomerism describe optical isomers as non-superimposable mirror images about an organic chiral

centre: four different groups attached to a carbon atom identify chiral centres in a molecule of given structural formula explain that optical isomerism and E/Z isomerism are different types of stereoisomerism

F324 Amino Acids & Chirality

The –NH2 group, like any amine, is able to act as a base by using the lone pair on the N atom to accept a proton. The –COOH group, like any carboxylic acid, is acidic. It can act as a proton donor, and undergoes the characteristic reactions of a carboxylic acid e.g. esterification.

ZwitterionsThe acidic carboxylic acid group can donate a proton to the basic amine group. The result is an internal salt (a molecule having both a positive and a negative charge on different parts of the same molecule) known as a zwitterion.

A zwitterion has no overall charge.

Each amino acid has a characteristic pH called the isoelectric point at which it exists as a zwitterion. The exact value of pH depends on the nature of the R- group. Many amino acids have their isoelectronic point close to pH = 6, but you will be given the isoelectronic point for any exam questions needing you to use it.

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F324 Amino Acids & Chirality

Amphoteric propertiesAmino acids are amphoteric – which means they can react with both acids and bases.

In a solution with pH lower (more acidic) than the isoelectric point:The amino acid

-behaves as a base, - reacts with the acid (H+ ions) in the solution

e.g. H2N-CH2-COOH + H+ H3N+-CH2-COOHN.B. All –NH2 groups in the amino acid will accept a proton.

In a solution with pH higher ( more alkaline) than the isoelectric point:The amino acid

- behaves as an acid- reacts with the alkali (OH- ions) in the solution

e.g. H2N-CH2-COOH + OH- H2N-CH2-COO- + H2ON.B. All –COOH groups in the amino acid will donate a proton

Hint ! Read questions carefully. An equation in which the amino acid is acting as an acid would be the same equation as one in which the amino acid is reacting with a base.

Overall we can depict the situation as:

Practice:1) Glutamic acid has the formula HOOCCH2CH2CH(NH2)COOH with an isoelectronic point of pH 3.22. Write the formula for the ionic species of glutamic acid present at:

(a) pH 3.22 (b) pH 1(c) pH 13

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CH3

CH2

F324 Amino Acids & Chirality

Formation of peptides

Amino acids join together by peptide linkages to form peptides.

Two amino acids can join in a condensation reaction, with the elimination of water, to form two different dipeptides.

e.g. glycine can react with alanine to form a dipeptide like this:

But this is not the only STRUCTURAL ISOMER which could be formed. Above we reacted the –NH2 group of alanine with the –COOH group of glycine, but we could also have reacted the –COOH group of alanine with the –NH2 group of glycine:

Forming polypeptidesA polypeptide is a chain of amino acids joined together by peptide linkages. The chain is made by condensation reactions. As each amino acid is added a water molecule is eliminated. Proteins are simply long-chain polypeptides, generally with more than 50 amino acid units.

Drawing a section of a polypeptideJust like drawing a polymer section, there will be "open" bonds at either end of the section showing it continues beyond that which has been drawn. A section contains a whole number

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+ + H2O

Definitions: A peptide is a compound containing amino acids linked by peptide (amide) bonds. The number of amino acids is indicated by di-, tri- etc. prefixes.

A condensation reaction is one in which two small molecules react together to form a larger molecule, with the elimination of a small molecule such as water

F324 Amino Acids & Chirality

of amino acid units, so it is drawn with the end peptide linkages broken. One end of the section will have –NH- and the other will have a –CO- e.g. here is a section three amino acids long:

Hydrolysis of polypeptides and proteins

Polypeptides can be hydrolysed using acidic or alkaline conditions. The peptide linkages are broken, producing fragments which are related to the original amino acids.

Acid hydrolysisConditions: heat under reflux with 6 mol dm-3 hydrochloric acid for 24 hoursEffect: the chain breaks down to its component amino acids, which are in the

'positive ion' form (-NH2 groups protonated) due to the very acidic conditions.

e.g. the general principle can be illustrated using a dipeptide, but a protein can be broken down in the same way:

Alkaline hydrolysisConditions: react polypeptide with sodium hydroxide at just above 100°CEffect: the chain is broken down into amino acids in the form of their sodium salts

e.g the principle can be illustrated using a section of a polypeptide:

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Definition: hydrolysis involves the breaking of a bond by reaction with water.

F324 Amino Acids & Chirality

With the exception of glycine, amino acids are examples of molecules which show a different type of stereoisomerism to the E/Z or cis-trans stereoisomerism we met in AS Chemistry. This is optical isomerism.

Optical isomerism occurs when a carbon atom in a molecule has four different groups attached to it. For example, the C in an alanine molecule has –H, -CH3, -NH2 and –COOH attached to it, and therefore can show this type of isomerism.

Definition: optical isomerism occurs when a molecule has non-superimposable mirror images about a chiral centre. Optical isomers are also referred to as enantiomers.

Non-superimposable mirror images can be thought of as "left handed" and "right handed". The mirror image of an optical isomer cannot be turned around to any position which makes it the same as the original.

A chiral centre is a carbon atom in an organic molecule with all four attached groups being different. Rotations of the molecule about this centre cannot make one optical isomer the same as another.

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Chirality in Pharmaceutical Synthesis explain that the synthesis of pharmaceuticals often requires the production of a single optical isomer; explain that molecules prepared synthetically in the laboratory often contain a mixture of optical

isomers, whereas molecules of the same compound produced naturally by enzymes in living systems will often be present as one optical isomer only;

explain that the synthesis of a pharmaceutical that is a single optical isomer:- increases costs due to difficulty in separating the optical isomers,- reduces possible side effects and improves pharmacological activity;

explain that modern synthesis of a pharmaceutical with a single optical isomer is often carried out:- using enzymes or bacteria which promote stereoselectivity,- using chemical chiral synthesis or chiral catalysts,- using natural chiral molecules, such as L-amino acids or sugars, as starting materials.

Requirement, for chiral drugs and medicines, to minimise side effects for economical reasons and to reduce risk to companies from litigation.

Examples of chemical chiral synthesis: using cyclic strained molecules, reagents fixed to a polymer support with reactants flowing over them, and supercritical CO2.

F324 Amino Acids & Chirality

Optical isomers are chemically identical, although they have different physical properties, in that they rotate plane-polarised light in different directions.

A molecule can have more than one chiral centre. Each produces two optical isomers, so if a molecule has two chiral carbon atoms it will have two pairs of isomers (i.e. four optical isomers).

Practice:2) Which of the following molecules has chiral centers, and where are they: (Hint: The easiest way to see is to draw displayed formulae and look for carbons with four different attached groups)

CH3CH2CH2CH2CH2OH

CH3CH2CH(NH2)CH3

CH3CHClCH3

CH3CH(OH)Br

Chirality in drug synthesis

Molecules prepared synthetically in the laboratory often contain a mixture of optical isomers, whereas molecules of the same compound produced naturally by enzymes in living systems will often be present as one optical isomer only.

The synthesis of pharmaceuticals often requires the production of a single optical isomer. Pharmacological activity depends on the ability of the drug can interact with a receptor site in a biological system, and only one optical isomer has the correct stereochemistry to bind.

It is not always true that the one isomer has the desired pharmacological effect and the other is simply inactive – it may interact with the body in unintended and unexpected ways. Drug companies have now a greater awareness of the importance of chiral carbon atoms and the potential effects of optical isomers on the body, and drug testing agencies now insist on testing each enantiomer separately, rather than just testing the drug alone. It hasn't always been like this, and pharmaceutical companies have learned costly lesson:

Perhaps the best-known example is thalidomide (1954)- prescribed to prevent morning-sickness in pregnant women, and in some cold/flu

remedies- drug was chiral – one enantiomer had the required thereputic effect

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F324 Amino Acids & Chirality

- the drug was not marketed in the US because the FDA demanded further testing before licensing, and during this process the activity of the other enantiomer was discovered

- the mirror image led to deformities in developing babies – some 10,000 were affected in Europe

Another example was Seldane – one of the first antihistamine- used to relieve hayfever symptoms- chiral with one enantiomer having the required thereputic effect- after testing and licensing, it was found that the "inactive" isomer caused a potentially

fatal heart condition in some patients

Manufacturing single optical isomersThere is a requirement for pharmaceutical companies to manufacture chiral drugs and medicines (i.e. containing only one single optical isomers) to minimise the chance of side effects from the other optical isomer, and to reduce the risk to companies from litigation.

e.g. if thalidomide has been been used with only the correct single optical isomer, morning sickness would have been prevented without the deformities

Method 1: making a mixture of both isomers then separating themSynthesis of a pharmaceutical that is a single optical isomer can be done by using chiral chromatography, where a chromatography column is packed e.g. with an enzyme having receptor sites to bind one of the two isomers. This increases costs due to difficulty in separating the optical isomers, but reduces possible side effects and improves pharmacological activity (when a drug containing a mixture of two optical isomers is prescribed, half the drug is often wasted in the body because it is the inactive isomer – making a single optical isomer halves the drug dosage required)

Method 2: developing a synthetic route in which only one of the two isomers is madeModern synthesis of a pharmaceutical with a single optical isomer is often carried out using enzymes or bacteria which promote stereoselectivity, or using naturally-occurring chiral molecules, such as L-amino acids or sugars, as starting materials.

Alternatively, chemical chiral synthesis or chiral catalysts can be used. Examples of chemical chiral synthesis use cyclic strained molecules, reagents fixed to a polymer support with reactants flowing over them, and supercritical CO2.

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OHOH

COOH

F324 Amino Acids & Chirality

Practice: 3) Find the chiral centre in these molecules

Seldane

Ibuprofen

N.B. Ibuprofen has one active optical isomer which controls pain effectively by blocking messages to the brain and reducing swelling and inflammation. The other isomer is fortuitously converted into the active isomer in the body, so the whole dose is active. This means ibuprofen can be manufactured more cheaply, as a mixture of isomers.

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F324 Amino Acids & Chirality

Answers to practice questions:

1) Glutamic acid has the formula HOOCCH2CH2CH(NH2)COOH with an isoelectronic point of pH 3.22. Write the formula for the ionic species of glutamic acid present at:

(a) pH 3.22 HOOCCH2CH2CH(NH3+)COO- i.e. the Zwitterion

(other COOH group is unaffected)

(b) pH 1 HOOCCH2CH2CH(NH3+)COOH (-NH2 group protonated, both COOH

unaffected)

2) Which of the following molecules has chiral centers, and where are they:a) CH3CH2CH2CH2CH2OH - no

b) CH3CH2CH(NH2)CH3 - yes 3rd C from the left is chiral

c) CH3CHClCH3 - no

d) CH3CH(OH)Br - yes 2nd C from left is chiral

3) Practice finding the chiral centre

Seldane

Ibuprofen

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