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

PART 14 ORGANIC ISOMERISM and Stereochemistry Revision Notes

Part 14.3 Optical Isomerism (R/S isomers) - an introduction

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 * amino acids-proteins-enzymes (separate page)

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


When two compounds have the same molecular and structural formula BUT can have mirror image forms which are NOT superimposable on each other. The non-superimposable mirror image isomers are called optical isomers (or enantiomers). The organic molecule must 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 below).

Chirality is the property of 'handedness' i.e. right 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 molecule exhibits chirality only if all four atoms/groups are different, and then optical isomers/non-superimposable mirror images/enantiomers can exist!

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

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.)

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 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.)

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.

Examples of molecules which will exhibit chirality, R/S optical isomerism, i.e. have a chiral carbon via which non-superimposable mirror image forms can exist i.e. enantiomers or R/S optical isomers - see if you can spot the chiral carbon and in some cases more than one!

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

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

2-bromo-3-chlorobutane, (c) doc b, (c) doc b has two chiral carbons

1,1,2-trichlorocyclohexane, (c) doc b 

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 b ,alcohols and ether structure and naming (c) doc b

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

(c) doc b3-iodobutanone   and   CH3COCH(C6H5)CH3 3-phenylbutan-2-one

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

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

3-aminohexane, (c) doc b, (c) doc b

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

2-hydroxypropanenitrile, CH3CH(OH)CN

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 from natural sources e.g. CH3CH(NH2)COOH, is called 2-aminopropanoic acid (the amino acid alanine, R = CH3). The alpha means a '2-amino' carboxylic acids, i.e. the 1st carbon to which a substituent group like NH2 can be attached.  CH3CH(NH2)CH2COOH is 3-aminobutanoic acid, old name, beta amino-butyric acid, beta meaning on the 2nd possible carbon for a substituent group.

All the alpha-amino acids obtained from proteins are optically active except glycine (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-

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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 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 Thalidomide tragedy and some important concepts in drug design

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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. I think that the Thalidomide was 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 occur 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.

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

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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


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 Dextro form becomes a Laevo form).

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

(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 possible optical isomer. The two optically activities cancel each other out, so zero rotation of plane polarised light. 

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

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


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

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



INDEX of isomerism & stereochemistry of organic compounds notes

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