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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

amino acids-proteins-enzymes (separate page)

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


Introduction

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.

Note one of the image conventions to represent a 3D molecule.

A Ca4 molecule e.g. methane CH4  (all four atoms bonded to the carbon the same)

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)

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)

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  (three different atoms bonded to the carbon)

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

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.

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).

isomers 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 above and below). The carbon atom is also referred to as a stereocentre.

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.

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 - the 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 balkanes structure and naming (c) doc b

3-methylpent-1-ene, alkenes structure and naming (c) doc balkenes 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   , two chiral carbons

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

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 the ionic forms are optically active too!

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 of R/S isomers 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-

(c) doc b isomersR/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 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. 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.

(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


 

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-

(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!)


Case study 6 Carvone

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

Your taste receptors respond different to the two different 3D shapes.


Case study 7 Ibuprofen

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

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

 


  Case study 8 Asparagine

Asparagine has three functional groups. From left to right: amide (CONH2), primary amine (-NH2) and carboxylic acid (-COOH).

? notes pending


Case study 9 Limonene

Limonene belongs to an unsaturated cyclic hydrocarbons called terpenes. 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).

?  notes pending


Case study 10 Penicillamine

?  notes pending


Case study 11 ?


 


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

explain more on amino acids


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