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(c) doc b isomers

Part 14.3 R/S Isomerism (optical isomerism) - an introduction

Doc Brown's Advanced A Level Organic Chemistry Revision Notes - Help in Revising Advanced Organic Chemistry

PART 14 ORGANIC ISOMERISM and Stereochemistry Revision Notes

What is chirality? What is a chiral carbon atom (an 'asymmetric carbon') On this page optical isomerism, now known as R/S isomerism is explained and examples of optical or R/S isomers (called enantiomers) are described including the terms enantiomers, enantiomerism, optical activity, polarimeter, racemate (racemic mixture) and how to assign the R or S isomer.

Case studies of structure, naming, formation, properties and stereochemical consequences of optical/geometrical isomerism


INDEX of isomerism & stereochemistry of organic compounds notes



14.3 R/S Stereoisomerism - Optical Isomerism (R/S enantiomerism)

Introduction below, then case studies: 1 amino acids * 2 alanine synthesis * 3 lactic acid synthesis * 4 Thalidomide

5 nucleophilic substitution of halogenoalkanes * 6. Carvone * 7. Ibuprofen * 8. Asparagine * 9. Limonene  * 10. Penicillamine

11. Enzymes and drugs - the stereospecific nature of their chemistry

amino acids-proteins-enzymes (separate page)

The IUPAC nomenclature R/S designation for absolute configurations of enantiomers (optical isomers)


Introduction - preferably exploring structures with a molecular model kit and spotting R/S isomers

Ball and stick models and general formulae to match the structures 1. to 6. (and the table below).

1. Ca4       2. Ca3b      3. Ca2b2      4. Ca2bc      5. and 6. non-superimposable mirror images of a Cabcd molecule

Thought experiment:

Take any of the models 1. to 4. and rotate 180o it to make a mirror image. Then rotate it a further 180o and you are back to where you started, yes?

You will find model molecules 1. to 4. have a plane of symmetry (see paper/screen exercise in next section).

Therefore mirror images of models 1. to 4. are superimposable and cannot be stereoisomers.

However, in the case of models 5. and 6., with four different groups attached to the central carbon atom, if you do the same thing, you cannot rotate one to give the same 3D spatial arrangement of the other. Therefore they are non-superimposable mirror images of the same molecule (same molecular and structural formula). They only differ in their 3D spatial arrangement of atoms and they are known as R/S isomers. They are also known as optical isomers (explain later) because R/S isomerism (R/S stereoisomerism) is also known as optical isomerism. The term R/S is preferred these days, but lots of 'old' terms are still in general use!

Of course its much better to the experiment for real with a molecular model kit, BUT, you don't get one in the exam!

The above exercise is now repeated, as in an exam, showing how to draw 2D images of 3D molecules!

Mirror images of the molecule Comments - a-d refer to the atoms bonded to the central carbon atom
First consider various possibilities for molecules consisting of a central saturated carbon atom with four atoms or groups attached to it by single bonds, C-a, C-b, C-c and C-d.

Atoms/groups a to d can be all the same, all different and anything in between! All the bond angles will be ~109o because of the tetrahedral arrangement of the four bonds emanating from the central carbon atom.

This is one of the image conventions to represent a 3D molecule in 2D.

A Ca4 molecule e.g. methane CH4  (all four atoms bonded to the carbon the same). The molecule has a plane of symmetry through the H-C-H bonds.

A highly symmetrical molecule. The mirror images are identical i.e. one mirror image is super-imposable on the other. All the H-C-H bond angles are 109.5o for the perfect tetrahedral shaped molecule.

The argument would be the same for CF4, CCl4, CBr4 and CCI4.

A Ca3b molecule e.g. fluoromethane CH3F  (two different atoms bonded to the carbon). The molecule has a plane of symmetry through the H-C-F bonds.

Not quite as symmetrical as CH4, but there is a plane of symmetry originating from the planar arrangement of the H-C-F bond with respect to the other two hydrogens. Therefore the mirror images can be super-imposed on each other - the mirror images are identical.

The argument would be the same for CH3Cl, CH3Br and CH3I

A Ca2b2 molecule e.g. difluoromethane CH2F2  (two different atoms bonded to the carbon). The molecule has a plane of symmetry through the H-C-H or F-C-F bonds.

Not quite as symmetrical as CH4, but there is a plane of symmetry originating from the planar arrangement of the F-C-F bond with respect to the two hydrogens (or H-C-H with respect to the 2 fluorines). Therefore the mirror images can be super-imposed on each other - the mirror images are identical. You can rotate one round to make the other.

The argument would be the same for CH2Cl2, CH2Br2 and CH2I2

A Ca2bc molecule e.g. chlorofluoromethane CH2ClF. Even with three different atoms bonded to the carbon, the molecule still has a plane of symmetry through the Cl-C-F bonds.

Even less symmetrical than a Ca2b2 molecule, but there is a plane of symmetry originating from the planar arrangement of the Cl-C-F bond with respect to the other two hydrogens. Therefore the mirror images can be super-imposed on each other - the mirror images are identical. Again, you can rotate one round to make the other.

A Cabcd molecules e.g. bromochlorofluoromethane CHBrClF

This molecule has no plane of symmetry.

We have now arrived at a molecule where four different atoms are attached to the central carbon atom. No matter which way you rotate one molecule with respect to the other, you cannot super-impose the mirror images on each other.

This molecule exhibits R/S isomerism (optical isomerism). The two isomers (the R and S isomers (optical isomers) are called enantiomers.

This is another example of stereoisomerism - they have identical structural formula, but differ in the spatial arrangement of the atoms.

(c) doc b For the rest of the page think in general terms of molecules with four different groups bonded to a carbon atom. The crucial carbon atom is known as an symmetric or chiral carbon atom - the origin of two non-identical, non-superimposable mirror image forms. R, R', R" and R''' must all be different, but they can be -H, -alkyl, -aryl, -halogen, -O-R, -NH2 i.e. anything that can form a single covalent bond with carbon.
How do we assign absolute R/S configuration?

Which is the R isomer? Which is the S isomer?

You need to know the Cahn-Ingold-Prelog priority sequence rules.

Priority in this case is easy to work out, just 4 atomic numbers!

Priority: 35Br  >  17Cl >  9F  > 1H

Imagine looking down vertically down at the carbon atom, then down the through the carbon atom to the atom of lowest priority (H here). view the three other atoms in the two possible sequences. This viewing can be equated with looking down on a steering wheel.

If the decreasing priority order is clockwise it is the R isomer.

If the decreasing priority order is anticlockwise it is the S isomer.

I've repeated the priority rule explanation further down the page.

This is R/S absolute configuration assignment is NOT needed for UK A Level students! BUT make sure you can do good '3D' diagrams of optical isomers - mirror image forms - enantiomers AND be able to spot the chiral carbon(s) - chiral centre(s)

 


Summing up so far and the properties and separation of R/S isomers

When two compounds have the same molecular and structural formula BUT have mirror image forms which are NOT superimposable on each other they exhibit R/S isomerism (optical isomerism).

isomersThe non-superimposable mirror image isomers are called optical isomers (or enantiomers). The organic molecule usually possess an asymmetric or chiral carbon, to which four different groups are bound in a tetrahedral bond arrangement (shown as R, R', R'' and R''' in the diagram above and below).

The asymmetric carbon atom is also referred to as a stereocentre or, more specifically, the chiral carbon.

Chirality is the property of 'handedness' i.e. right hand and left hand, in this case a molecule has two non-superimposable mirror images of each other.

Most examples you come across are organic molecules and based on the tetrahedral arrangement of four single covalent bonds emanating from a carbon atom. In the example below the R's can be H, alkyl, aryl, halogen, -COOH, -NH2, etc. etc.!

The two isomers have identical physical properties such as melting point, solubility and density BUT their crystalline forms will be mirror images, AND, importantly, for the same concentration of solution, they will rotate the plane of polarised monochromatic light to the same extent BUT in opposite directions (+xo clockwise, dextrorotatory (D) or -xo anticlockwise, laevorotatory (L)), a feature known as optical activity.

The D and L designation of optical isomers (enantiomers) predates the IUPAC R/S system, no change in the +/- rotation notation! .

 

A racemic mixture (racemate) consists of an equimolar mixture of both enantiomers and is therefore optically inactive, i.e. one isomer cancels out the rotation of plane polarised light caused by the other isomer. (Do NOT say it does not contain optically active molecules etc.)

 

Measurement of the rotation of plane polarised light

A polarimeter is an instrument for measuring the rotation of plane polarised light by a solution containing an optically active compound. The monochromatic light, e.g. the yellow-orange light from a sodium lamp, prior to passing through the solution, passes through special Nicol prism to produce polarised light. This means the electromagnetic oscillations occur in a narrow plane instead of through 360o. After passing through the solution, the light passes through a 2nd Nicol prism that acts as the analyser. The eyepiece can be rotated to measure the rotation angle produced by the solution of the enantiomer(s).

 

Physically the isomers are identical e.g. same melting point, density, solubility i.e. the mirror image forms exhibit the same inter-molecular forces between themselves or in there interaction with solvents (same thermodynamically as in ΔHsolution, ΔHcomb, ΔHfusion etc.).

However, there can be significant chemical differences due to the asymmetry of the molecule - we are now talking stereoisomerism influencing stereochemistry!

 

Chemically their properties are identical unless there is some stereospecificity in the reaction,

e.g. the 3D requirements of a substrate 'docking' into an enzyme or reaction with an optical isomer of another molecule. Many of the subtleties of enzyme-substrate interaction (key and lock mechanism) are due to the behaviour of a particular optical isomer.

The sorts of chemical differences that can arise are discussed in 10 case studies of stereoisomerism in the last section of this page.

 

Separating optical isomers - separating the enantiomers from a racemate mixture

The separation of enantiomers, known as resolution (resolving the mixture) is very difficult and only be done with a chiral agent to give products with e.g. different physical properties like solubility, enabling separation of enantiomers by fractional crystallisation. This process must involve the formation of an intermediate stereospecific compound from which the desired enantiomer product must be obtained.

The famous scientist Louis Pasteur noticed that the crystals of sodium ammonium tartrate (sodium ammonium 2,3-dihydroxybutanedioate) occurred in mirror image shapes. Using tweezers, he actually picked out and separated the two forms. When dissolved in water, they rotated plane polarised light in opposite directions, the different rotations of the + and the - isomers. Perhaps you only thought he was famous for the pasteurisation of milk!

 


Examples of molecules which will exhibit chirality, R/S optical isomerism

i.e. molecules that have a chiral carbon via which non-superimposable mirror image forms can exist - the enantiomers or R/S optical isomers - see if you can spot the chiral carbon and in some cases more than one! (and I haven't marked the chiral carbons on the images!). Unless otherwise stated, all the molecules have one chiral centre.

3-methylhexane, alkanes structure and naming (c) doc balkanes structure and naming (c) doc b

3 different alkyl groups and a hydrogen attached to the chiral carbon.

3-methylpent-1-ene, alkenes structure and naming (c) doc balkenes structure and naming (c) doc b

3 different hydrocarbon groups and a hydrogen attached to the chiral carbon.

2-bromo-3-chlorobutane, (c) doc b(c) doc b has two chiral carbons, so there will be 4 R/S stereoisomers.

1,1,2-trichlorocyclohexane, (c) doc b has two chiral carbons, so there will be 4 R/S stereoisomers (2 pairs of R/S isomers).

In these last two examples, for each chiral centre you will a pair of R/S isomers giving a + and - rotation of plane polarised light.

Butan-2-ol, alcohols and ether structure and naming (c) doc b,    alcohols and ether structure and naming (c) doc b

2-methoxybutane, alcohols and ether structure and naming (c) doc balcohols and ether structure and naming (c) doc b

(c) doc b , 3-iodobutanone   and   CH3COCH(C6H5)CH3   3-phenylbutan-2-one

3-aminohexane, (c) doc b,   (c) doc b

2-methylbutanal, aldehydes and ketones nomenclature (c) doc b,   aldehydes and ketones nomenclature (c) doc b  

2-chloropropanoic acid, (c) doc b,   (c) doc b

2-methylbutanoic acid , (c) doc b,   (c) doc b

2-aminopropanoic acid, (c) doc b  (c) doc b  or  (c) doc b   (c) doc b

the ionic forms have the same chiral centre and therefore are optically active too!

2-hydroxypropanenitrile, CH3CH(OH)CN  

Structural isomer note on the last five examples of molecules with a chiral carbon:

For 2-methylbutanal, 2-chloropropanoic acid, 2-methylbutanoic acid, 2-aminopropanoic acid and 2-hydroxypropanenitrile, the 3- substituted isomer will NOT exhibit R/S isomerism - check them out?

The IUPAC nomenclature R/S designation for absolute configurations of enantiomers (optical isomers)


 

Case study 1 Alpha amino-acids

Alpha amino acids like RCH(NH2)COOH below, are classic examples of R/S isomers from natural sources.

e.g.

CH3CH(NH2)COOH, is called 2-aminopropanoic acid (amino acid alanine, R = CH3). The middle carbon is the chiral carbon.

R/S optical isomers of 2-aminopropanoic acid alanine

The alpha means a '2-amino' carboxylic acid, i.e. the 1st carbon to which a substituent group like NH2 can be attached, but is the 2nd carbon in the chain because carbon atom 1 is part of the highest ranking group).

CH3CH(NH2)CH2COOH is 3-aminobutanoic acid, old name, beta amino-butyric acid, beta meaning on the 2nd possible carbon for a substituent group. In this case it is carbon atom that is chiral.

All the alpha-amino acids obtained from proteins are optically active except glycine (aminoethanoic acid, R = H), 2-aminoethanoic acid, H2NCH2COOH, because it has no chiral/asymmetric carbon atom. In aqueous solution, and in the solid state, they predominantly exist as zwitterions, the ionic form derived from proton transfer from the carboxylic group onto the amino group.

RCH(NH2)COOH (c) doc b RCH(+NH3)COO-

(c) doc b isomers R/S isomers in the non-ionic molecular form (R = CH3 for alanine)

Comparing 'natural' and 'laboratory' synthesis

When molecules capable of exhibiting optical isomerism are obtained from natural sources, they usually consist of one of the possible isomers (one of the enantiomers) and on extraction, purification and isolation, they show optical activity (that is rotating the plane of polarised light in a polarimeter tube). This is due to the need for stereospecific structures from enzymes to proteins. The '3D' stereospecificity of enzyme sites is discussed in section 6.

However, when the same compound is synthesised in the laboratory, it often consists of an equimolar mixture of the two optical isomers. This is known as a racemic mixture and it is optically inactive due to one isomer cancelling out the optical effect of the other.

Warning: It is wrong to say that R/S optical isomers are not, or cannot be formed in laboratory synthesis!

 Its difficult, but no impossible, using very sophisticated synthesis techniques.

The most common explanation for the production of a racemic mixture lies in understanding the mechanisms of the laboratory synthesis reactions. For example, if a carbocation is formed, which has three C-R bonds in a trigonal planer arrangement, the reagent molecule or ion (electron pair donor) can attack on either side with equal probability. So when a possible chiral carbon molecule is formed in many a laboratory synthesis, it tends to be an equimolar mixture of the two spatial possibilities or enantiomers. (see carbocation mechanisms of haloalkane substitution reactions, addition reactions of aldehydes/ketones, and below, case studies 2 and 3).

However, since the 1990's the problem is being tackled by the use of chiral auxiliary molecules.


 

Case study 2 Synthesis of the amino acid alanine

2-aminopropanoic acid (the amino acid alanine) when extracted from broken down protein will show optical activity because it will consist of only one of the optical isomers, as it was produced, and used in protein formation, by stereospecific enzymes. It can be produced in the laboratory/industry by a two stage synthesis e.g.

(1) CH3CH2COOH  + Cl2 ==> CH3CHClCOOH + HCl

free radical chlorination of propanoic acid (no optical isomers)  with chlorine/uv gives 2-chloropropanoic acid which does exhibit optical isomerism (the reaction also forms isomeric 3-chloropropanoic acid).

(2) CH3CHClCOOH + 2NH3 ==> CH3CH(NH2)COOH + NH4+ + Cl-  

treating 2-chloropropanoic acid with excess conc. ammonia gives 2-aminopropanoic acid, which again, can exhibit optical isomerism.

In stage (1) the chlorine radical could abstract/substitute either of the two middle H's with equal probability and therefore a racemic mixture is likely to result.

OR if stage (2) went via a carbocation (with a trigonal planar bond arrangement, SN1 mechanism), substitution can take place by the NH3 molecule hitting either side of the carbocation 'centre' with equal probability.

Therefore either step could give an equimolar mixture of the possible optical isomers.

For more details on reaction (2) see carbocation mechanisms of haloalkane substitution reactions,.


 

Case study 3 Natural and synthetic lactic acid

Optically active 2-hydroxypropanoic acid (lactic acid) is formed by the fermentation of sugars using lactobacilli and one enantiomer tends to dominate. In the laboratory it can be synthesised in two stages as follows, but an optically inactive racemic mixture of the two enantiomers is formed. In stage (1) the nucleophilic cyanide ion can attack the slightly positive carbon of the polarised >C=O (which has a trigonal planar bond arrangement), on either side, with equal probability. This produces an equimolar mixture of the optical isomers of 3-hydroxypropanenitrile.

(1) CH3CHO + HCN (c) doc b CH3CH(OH)CN

nucleophilic addition of hydrogen cyanide to ethanal

(2) CH3CH(OH)CN + 2H2O + H+ (c) doc b CH3CH(OH)COOH + NH4+  

hydrolysed by refluxing with dilute acid

For more details on reaction (2) see addition reactions of aldehydes/ketones.


 

Case study 4 The Thalidomide tragedy and some important concepts in drug design

(c) doc b

The two enantiomers of an optically isomeric drug can have very different effects administered separately, or as a racemic mixture. In the case of Thalidomide, one enantiomer alleviates morning sickness in pregnant women, which is what the drug had been originally designed for.

Unfortunately, with tragic results, the other mirror image enantiomer causes genetic damage in the fetus resulting in physical deformities of the limbs.

The Thalidomide was originally administered as a racemate (racemic mixture 1:1 ratio of the enantiomers). Even if the 'safe' isomer can be separated to high degree of purity, it was only found later that an isomerisation reaction occurs forming the harmful mirror image enantiomer in vitro i.e. in situ in the body.

The pharmacophore is the part of the molecule which is primarily responsible for the pharmacological action of the drug. The chiral carbon must be part of the 'pharmacophore' of the thalidomide molecule.

Therefore, in the synthesis of pharmaceuticals, it is highly desirable, if not easily achievable, to produce drugs of a chiral nature, containing only the single and most effective enantiomer. This results in smaller doses, reducing side effects and overall improving pharmacological activity.

Chiral auxiliary synthesis:

One way round the stereoisomer problem encountered in Thalidomide, is to use a chiral auxiliary molecule X which converts a non-chiral starter/substrate molecule S into just the desired enantiomer, A or B. This avoids the need to separate enantiomers from a racemic mixture. X works by attaching itself to the non-chiral molecule S to produce the stereochemical intermediate structure required to make the reaction go in the desired 'stereochemical' direction (i.e. the desired enantiomer). Once the new intermediate stereoisomer molecule X-A or X-B is formed, the chiral auxiliary molecule X can be removed and recycled leaving the desired enantiomer required A or B.

So a chiral auxiliary is a molecule that is temporarily incorporated into an organic synthesis where its asymmetry allows the formation of a chiral intermediate followed by selective formation of one of two enantiomers depending on the reagent and/or reaction conditions. The sequence shown in diagrammatic form below.

(c) doc b

e.g. the anti-cancer drug TAXOL is a very chiral molecule indeed and requires extremely sophisticated synthetic routes!

(c) doc b

The action of biologically active chemicals like drugs is very much related to their interaction with receptor sites.  The extent and nature of the three dimensional interaction involved can be determined by molecular size or shape, chemical bonding or intermolecular force attraction as well as spatial orientation. It is therefore not surprising that both enzymes and pharmaceutical products like drugs show considerable stereospecificity in terms of what they will interact with and therefore .

See also combinatorial chemistry concerning drug synthesis

 

Pharmaceutical costs due to chemical stereospecificity!

Because the enantiomers can have different pharmacological activities, drug companies have a real problem in synthesising the most effective isomer. It may be relatively cheap to make a racemic mixture and this can provide effective medical treatment as long as the 'inactive' isomers doesn't have any harmful side-effects. If one enantiomer is harmful, but the other is so effective as to be worth the effort of synthesising it by stereospecific reactions, then the cost of production is much higher, and the cost  passed onto to the medical services.

Apparently half of all commercially available drugs contain at least one chiral centre.

Many products from natural sources consist of one enantiomer only, compared to many synthetic products consist of a racemic mixture of the enantiomers and many marketed with this composition - but, sadly, other instances like the thalidomide tragedy, have, and will happen again, without very strict regulation and thorough testing of the pharmaceutical product.


 

Case study 5 Nucleophilic substitution in halogenoalkanes

e.g. The hydrolysis of a halogenoalkane with three different groups (R, R' and R") and the halogen (X) attached to the chiral carbon *C (using aqueous sodium hydroxide reagent). The situations can be complicated depending on the mechanism. Here we will assume the starting halogenoalkane consists only one of the possible optical isomers (enantiomers). the starting halogenoalkane consists only one of the possible optical isomers (enantiomers).

(a) If the SN2 mechanism prevails, that is a single step bimolecular collision of the reactants (without intermediate carbocation formation), a single optical isomer of the alcohol is formed. In fact the spatial orientation about the chiral carbon is inverted, as is the optical activity in terms of the direction plane polarised light is turned (e.g. a R isomer becomes an S isomer - assuming no change in the priority order in the substituted product).

i.e. RR'R''*C-X + OH- (c) doc b RR'R''*C-OH + X-

organic reaction mechanisms SN2 mechanism for RX + OH- ==> ROH + X-

Unlike in the SN1 mechanism (b) below , in the case of the SN2 mechanism (e.g. mechanism 33 above), racemisation does NOT take place and chirality and optical activity is completely preserved in the molecule, BUT inversion takes place i.e. the absolute 3D configuration of the product is completely opposite to that of the reactant.

Stereochemically the most successful line of attack for SN2 substitution, is if the nucleophile hits the carbon of the C-Hal bond on the opposite side to the halogen atom. The result has been likened to an umbrella being blown inside out in a gale! The three single bonds for the -CRR'R'' are pushed through and so the configuration inverted!

For an optically active halogenoalkane reactant, the retention of complete optical activity in a nucleophilic substitution reaction is evidence of the SN2 bimolecular mechanism.

 

(b) If the SN1 mechanism prevails, that is two steps via a carbocation intermediate, a racemic mixture (optically inactive) equimolar mixture of the two enantiomers is formed e.g.

(i) RR'R''*C-X (c) doc b RR'R''*C+ + X-

(ii) RR'R''*C+ + OH- (c) doc b RR'R''*C-OH

This is because the carbocation formed in the rate determining step (b) (i), has a trigonal planar arrangement of C-R bonds around the C+ carbon, so the hydroxide ion (or water) can attack each side of the carbocation with equal probability, giving equal amounts of each of the two possible R/S mirror image optical isomer. The two optically activities tend to cancel each other out, so zero rotation of plane polarised light. 

organic reaction mechanisms SN1 mechanism for RX + OH- ==> ROH + X-

In the SN1 carbocation mechanism (e.g. mechanism 1 above), the three bonds of the R groups of the carbocation formed in step (1), are in a trigonal planar arrangement >C-. This means the nucleophile (e.g. OH- or H2O) can attack the carbocation with equal probability on each side. This results in a tendency for a racemic mixture to form, that is an optically inactive mixture of equal amounts of the two optical isomers.

(What you actually get in practice is a significant reduction in optical activity in the product)

For an optically active halogenoalkane reactant, the considerable reduction in optical activity in a nucleophilic substitution reaction is evidence of the SN1 unimolecular mechanism i.e. the formation of a trigonal planar carbocation.

 

For detailed discussions see the nucleophilic substitution mechanisms part 2 halogenoalkanes page.

Quick scribbled Question on Optical Isomer and Chiral Carbon 'spotting' (and answers!)


Case study 6 Carvone

Many enantiomers occur naturally e.g. carvone is an unsaturated cyclic ketone.

One alkene group (>C=C<) is in the ring and another in a side chain.

One of the R/S isomers of carvone smells and tastes of spearmint leaves (its in spearmint oil) and the other R/S isomer tastes and smells of caraway seeds (in caraway seed oil).

Your taste receptors respond different to the two different 3D shapes, so your taste receptors are exhibiting stereospecificity.


Case study 7 Ibuprofen

Ibuprofen is a widely used non-steroidal anti-inflammatory drug used for treating pain, fever, and inflammation.

This popular analgesic has just one chiral centre.

The molecule is based on a benzene ring and two aliphatic side chains, one of which ends in a carboxylic acid group.

One enantiomer of Ibuprofen is much more effective than the racemic mixture, i.e. one enantiomer is more effective than the other. However, somewhat fortunately, the body converts the less active enantiomer into the more active enantiomer!


  Case study 8 Asparagine

Asparagine has three functional groups and one chiral centre.

From left to right: amide (CONH2), primary amine (-NH2) and carboxylic acid (-COOH).

To our taste buds, one enantiomer of asparagine tastes sweet and the other enantiomer tastes bitter.


Case study 9 Limonene

Limonene belongs to an unsaturated cyclic hydrocarbons called terpenes with one chiral centre.

The molecule contains two alkene groups (>C=C<), one is in the ring and another in a side chain (same as in carvone case study 6).

One enantiomer of limonene smells of oranges and the other of lemons.

 


Case study 10 Penicillamine

Penicillamine has three functional groups and one chiral centre.

From left to right: thiol (-SH), primary amine (-NH2) and carboxylic acid (-COOH).

D-penicillamine is used to treat rheumatoid arthritis, however, L-penicillamine is toxic and caused optic nerve damage. The drug was withdrawn because the racemic mixture had been used. However, you can manufacture D-penicillamine from penicillin thus avoiding the bad side-effects from using the penicillamine racemate.

 


Case study 11 Drawing a parallel between enzyme function and the pharmacological action of certain drugs

The effective action of all enzymes and many drugs relies on the stereospecificity of their chemistry.

How do enzymes work?

A substrate molecule is a reactant which is to be changed into the product by way of the specific enzyme.

The substrate molecule (or molecules) must fit neatly into the active site on an enzyme and weakly bond to it.

The active site on the protein structure of an enzyme is a precise 3D conformation of atoms.

The enzyme, or more specifically, the active site, is referred to as the 'lock', and in an analogy with door locks, the substrate molecules are referred to as the 'key or keys'. The action by which enzymes function as called the 'key and lock' mechanism. This is illustrated below.

It is at the active site the chemical change from substrate to product takes place and its shape is very important.

Many biochemistry reactions either involve synthesis of a larger molecule by joining smaller ones or breaking down and splitting a larger molecule into smaller ones.

Each enzyme is shaped precisely to accept the substrate molecules, otherwise the reaction will NOT take place, which is why a particular enzyme can only catalyse a specific reaction. The substrate must fit into the active site.

This means the enzyme catalysed reaction is stereospecific and only the right substrate will fit into the active site.

If the enzyme is not the right shape e.g. the protein structure-active site is damaged, the substrate molecule cannot 'key in' so the enzyme cannot function and the reaction does not take place. This protein structure damage is referred to as a denaturing of the enzyme. It can be caused by too high a temperature or the medium may be too acid (too low a pH) or too alkaline (too high a pH) - see later section on factors affecting the rate of enzyme reactions.

The four images above use ball and stick models to try and illustrate the specificity of enzyme - substrate reactions, or indeed the action of an enzyme inhibiting drug.

Image 1. shows the configuration of a pair of non-superimposable mirror image molecules. The yellow, purple, grey and green balls represent four different atoms or groups attached to the central chiral carbon (asymmetric carbon stereocentre). Their particular nature is irrelevant to the argument here.

Image 2. is a fictitious section of a (usually quite large) protein molecule that acts as an enzyme. The upper ring of atoms e.g. carbon, nitrogen, oxygen and hydrogen forms the 'rim' of the 'cradle' of the active site below it, into which the enzyme substrate or drug must fit. I wish you to assume that the three purple, yellow and grey 'quads' of balls represent the points on the active site where the intermolecular bonding forces will operate to hold the substrate molecule in place to effect the chemical transformation.

Image 3. shows the substrate molecule locked in place via the purple-purple, yellow-yellow and grey-grey intermolecular bonding forces. We have now formed the enzyme-substrate complex because the 3D nature of the substrate molecule matches the 3D conformation of the 'docking site' - the active site on the enzyme. The big S represents where the substrate molecule is locked into the active site.

Image 4. shows the mirror image of the substrate trying to 'dock in' but the colours do not match and so the substrate cannot be held on the active site and the enzyme cannot perform any chemical change on the molecule. The grey-grey interaction matches, but the yellow-yellow and purple-purple interactions do NOT.

Note: What my humble ball and stick 'art installations' don't show clearly, is the mirror image substrate might not even fit into the active site in the first place i.e. gain access into the 'cradle'. The active site on the enzyme is a precise 3D conformation to match the substrate or the pharmaceutical industry produced drug, must match i.e. with the right shape to fit in (more on the latter at the end). I need to build a much bigger model of enzyme and substrate to show the full 3D effect.

Both the respective 3D shapes of enzyme and substrate AND the intermolecular binding forces are important.

Therefore think of the 'matching colour' analogy here as a combination of the right shape fitting in AND being held sufficiently by the intermolecular bonding forces to effect the chemical change.

Since you don't get model kits in exams, I know refer you to 'key and lock' schemes of explanation below, while I work on the next model!

 

The following diagrams illustrate two examples of the 'key and lock' mechanism - how an enzyme works. It is sometimes quoted as a hypothesis, but there is a vast amount of evidence to show this mechanism is correct.

(Stage 1) is the 'docking in' of the substrate molecules into the active sites, they are held there sufficiently to allow the chemical transformation to take place.

(Stage 2) happens on the active site where the substrates are catalytically changed to products which are then released from the enzyme.

key and lock mechanism for synthesising a larger molecule from smaller molecules.

Sequence key e.g. for a larger molecule being made from two smaller molecules, perhaps a stage in protein synthesis

E = free enzyme (the 'lock'), S = free substrate reactant molecule (the 'keys')

ES = enzyme-reactants complex, EP = enzyme-product complex, E = free enzyme, P = free product

The diagram simulates two amino acids joined together to make a dipeptide, or you can just think of one of the substrate molecules being a longer partially made protein molecule and another amino acid is added to the end of the chain.

The shape of the 'purple and black' substrate molecules must match the shape of the active site to fit in and bond via (usually) intermolecular forces.

 

key and lock mechanism for producing smaller molecules from larger ones.

Sequence key e.g. for a larger molecule being broken down into two smaller molecules, perhaps in digestion where large carbohydrate molecules are broken down into small sugar molecules like glucose.

E = free enzyme (the 'lock'), S = free substrate reactant molecule (the 'key'),

ES = enzyme-reactant complex, EP = enzyme-products complex, E = free enzyme, P = free products

 Apart from water molecules, the diagram actually matches the hydrolysis of sucrose to glucose and fructose by the enzyme invertase.

C12H22O12  +  H2O  ===> C6H12O6  +  C6H12O6 

The shape of the blue' substrate molecule must match the shape of the active site to fit in and bond via (usually) intermolecular forces.

 

Note: If the wrong substrate CAN dock in, and his held too strongly by intermolecular forces, covalent or ionic bonding, the active site is no longer active and the enzyme reaction is blocked and stopped. This can happen with certain poisons which can irreversibly bind to an enzyme.

The enzyme reaction can be completely inhibited (usually irreversible) or its activity considerably decreased (reversible).

In terms of the diagrams above, an irreversible blocking won't even allow stage (1) to occur, so automatically blocking stage (2).

In terms of the diagrams above, a reversible blocking enzyme inhibitor will reduce the enzymes activity by inhibiting stage (1), but in doing so automatically inhibiting stage (2).

 

Examples of 'non-medical' enzyme inhibition (not usually very good for you!)

Nerve gas warfare agents can act in this way.

The controversial weed killer 'Glyphosphate' blocks a specific enzyme reaction in plant and bacterial cells and the organism dies as a consequence.

As regards the latter, 'evolution' is 'fighting back' and weed strains are emerging which are Glyphosphate resistant. Are we dealing with smart evolution of protein-enzyme here, preceded by mutation?

Arsenic compounds (arsenate(V) ion AsO43-) blocks an enzyme involving the phosphate(V) ion (PO43-). In effect the arsenate ion replaces the phosphate ion, thereby blocking the correct enzyme reaction. A potentially fatal example of excellent periodic table chemistry of Group 5/15.

Although not an enzyme reaction, carbon monoxide poisoning is due to the CO acting as a stronger ligand than oxygen and binds more strongly to a haemoglobin molecule and therefore indirectly inhibiting respiration.

Some heavy metal cations (e.g. mercury Hg2+) have a strong affinity for the groups like -SH, PO3-, -NH-, -NH2 and -COOH, all found in the structure of proteins including enzymes. These 'toxic' metal ions bind to the enzymes preventing them from working properly, stopping or altering their biochemical process. The metal ions change the 3D conformation of the active site on the enzyme.

 

Apart from poisoning effects, most of the discussion above has centred around the natural occurring biochemistry of cells.

BUT, pharmaceutical companies have developed drugs which are effectively enzyme inhibitors to treat certain medical conditions. So, many medicines are enzyme action inhibitors, but they may have to be of the reversible type.

To be pharmacologically active, the drug must have the right stereochemical structure to perform its 'medicinal' role.

Ibuprofen works by blocking the production of prostaglandins, substances that the body releases in response to illness and injury. Prostaglandins cause pain and swelling, or inflammation. They are released in the brain, and they can also cause fever. Ibuprofen's painkilling effects relies on reversibly blocking an enzyme reaction soon after taking a dose!

Penicillin functions by interfering with the synthesis of cell walls of reproducing bacteria. Penicillin inhibits an enzyme that catalyses the last step in bacterial cell wall biosynthesis. The defective cell walls cause bacterial cells to burst, but human cells are not affected because they have cell membranes, not cell walls. I presume penicillin is an irreversible enzyme inhibitor?

 

However, things are never simple in the world of pharmaceutical products ...

More on cost factors - both for the pharmaceutical industry and the patient!

With many pharmaceuticals there one enantiomer is more effective than another, it is very costly to produce the specific enantiomer using specific stereochemistry.

Enantiomers are difficult to separate because of their similar/identical physical or chemical properties. Special separation techniques must be employed to separate enantiomers. These include the use of:

stereospecific reagents in the preparation (very costly to make and use),

enzymes (automatically stereospecific in their action),

electrophoresis (but employs stereospecific reagent e.g. a protein gel),

chromatography (but the enantiomers must be complexed with a reagent prior to separation and then de-complexed to extract the desired enantiomer).

Even if one enantiomer is very effective, more so than the mirror image, it can still be effectively prescribed as long as the other enantiomer has no harmful side-effects.

If you can produce a concentrate of the most pharmacologically active enantiomer, you can reduce the patient dose, i.e. half won't be wasted. This also reduces the manufacturing cost too - less waste.

Most drugs are quite 'blunt' in their pharmacological action and most have some kind of side-effect, that may, or may not, affect the patient. The risks can be considerable, particularly if one enantiomer is ok, but the other induces other chemical side-effects with serious consequences. See the classic case of Thalidomide.

The cost of developing new pharmaceutical products is high and thorough (I hope) clinical trials add to the development costs. In some cases, whole projects may have to be abandoned if the trials show up serious side-effects.

 

ENZYMES - structure, function, optimum conditions, investigation experiments  (gcse biology notes)

See also Enzymes and Biotechnology (gcse chemistry notes)

and advanced notes on Enzyme kinetics (not needed by UK A Level students?)


The IUPAC nomenclature for R/S designation for absolute configurations of enantiomers (optical isomers)

This is R/S absolute configuration assignment NOT needed for UK A Level students! BUT make sure you can do good '3D' diagrams of optical isomers - mirror image forms - enantiomers.

Using the priority rules (Cahn-Ingold-Prelog priority sequence rules), a must read to follow this section on assigning the absolute structure of R/S isomers, so you deduce the priority order of all the atoms/groups attached to the central chiral atom and hence assign the configuration.

 That is a molecule with an asymmetric carbon atom with four different atoms/groups attached to it - which is the criteria here for optical isomers (enantiomers) to exist as a non-superimposable mirror image forms. The following two examples explain how the absolute configuration is expressed in the fill IUPAC nomenclature system.

Diagram explaining R/S optical isomerism enantiomer configuration nomenclature

Left diagram: R/S-bromochloroiodomethane: The priority order is I > Br > Cl > H. The 'steering wheel' approach. Imagine the 'steering wheel' is the C-H bond pointing away from you, and it must be the bond to the atom or group of lowest priority of the four atoms/groups (sometimes referred to as 'ligands').  The Cl, Br and I atoms form three points on the 'steering wheel'. For the R isomer configuration these three atoms decrease in priority when moving clockwise (R-bromochloroiodomethane). For the S isomer the priority of the atoms priority decrease if you move in an anticlockwise direction (S-bromochloroiodomethane).

Right diagram: R/S alpha-amino acids: The priority is NH2 (7N) > COOH (6C) > R (assumed priority here e.g. alkyl) > 1H

explain more on amino acids


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