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
14.3 R/S Stereoisomerism - Optical Isomerism (R/S enantiomerism)
amino acids-proteins-enzymes (separate page)
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).
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).
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.
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.
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
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,
Separating optical isomers - separating the enantiomers from a racemate mixture
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.
2-bromo-3-chlorobutane, , has two chiral carbons, so there will be 4 R/S stereoisomers.
1,1,2-trichlorocyclohexane, has two chiral carbons, so there will be 4 R/S stereoisomers (2 pairs of R/S isomers).
, 3-iodobutanone and CH3COCH(C6H5)CH3 3-phenylbutan-2-one
2-chloropropanoic acid, ,
2-methylbutanoic acid , ,
2-aminopropanoic acid, or
Structural isomer note on the last five examples of molecules with a chiral carbon:
Case study 1 Alpha amino-acids
Alpha amino acids like RCH(NH2)COOH below, are classic examples of R/S isomers from natural sources.
CH3CH(NH2)COOH, is called 2-aminopropanoic acid (amino acid alanine, R = CH3). The middle carbon is the chiral carbon.
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).
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.
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!
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
(2) CH3CHClCOOH + 2NH3 ==> CH3CH(NH2)COOH + NH4+ + Cl-
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 CH3CH(OH)CN
(2) CH3CH(OH)CN + 2H2O + H+ CH3CH(OH)COOH + NH4+
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
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.
e.g. the anti-cancer drug TAXOL is a very chiral molecule indeed and requires extremely sophisticated synthetic routes!
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 .
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.
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- RR'R''*C-OH + X-
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 RR'R''*C+ + X-
(ii) RR'R''*C+ + OH- 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.
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.
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.
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
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.
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.
Apart from water molecules, the diagram actually matches the hydrolysis of sucrose to glucose and fructose by the enzyme invertase.
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.
Examples of 'non-medical' enzyme inhibition (not usually very good for you!)
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.
However, things are never simple in the world of pharmaceutical products ...
More on cost factors - both for the pharmaceutical industry and the patient!
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.
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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