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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 &
Stereochemistry Revision Notes
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All my advanced A level organic
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All my advanced A level
isomerism and stereochemistry notes
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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.
Chirality and R/S isomerism explained
followed by case studies of structure, naming, formation, properties and
stereochemical consequences of R/S
isomerism
14.3 R/S Stereoisomerism - Optical
Isomerism
(R/S enantiomerism)
Introduction below, then case
studies of R/S isomerism:
14.3.0
INTRODUCTION
Some question
to answer!
Ball and stick models and
drawing 2D diagrams to explore the 3D significance of R/S
isomers
Summing up the
properties of R/S isomers and how you can separate them
Examples of molecules which will
exhibit chirality, R/S optical isomerism
Measuring the optical activity of R/S isomers (enantiomers) and
what is a racemate mixture?
Chemical consequences of R/S isomerism and how
can we separate R/S isomers?
Case studies of R/S isomerism
1
Amino acids *
2
Alanine synthesis *
3
Lactic acid synthesis
4a
The thalidomide
tragedy
* 4b. The need for modern chiral synthesis in the pharmaceutical industry
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
12. Nucleophilic addition to
aldehydes and ketones
13. Stereochemistry of SN2 bimolecular nucleophilic substitution
reactions
14. Quantitative examples of using polarimeter
to measure concentrations including kinetic investigations
15. Optical activity of relatively simple molecules
with more than one chiral centre
The IUPAC nomenclature R/S designation for absolute configurations of
enantiomers (optical isomers)
Definition of
diastereoisomers
Amino
acids-proteins-enzymes (separate page on their stereochemistry)
Introduction
- preferably exploring structures with a molecular model kit and
spotting R/S isomers
What is R/S isomerism? Why can R/S
isomers exist? What are non-superimposable mirror image forms?
Why was R/S isomerism called 'optical
isomerism'? Why can molecules turn the plane of a polarised light
beam?
How do we measure the optical activity of a molecule?
Where does R/S isomerism fit in the big
picture of isomerism? (see the diagrams below!)
R/S isomerism is when a molecule of
the same molecular formula and same structural formula can exist in
two non-superimposable mirror image forms (once called
'optical isomerism).
Using ball and stick models and drawing
2D diagrams to explore the 3D significance of 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 (if you haven't got access
to a ball and stick model kit:
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 R/S stereoisomers.
However, in the case of models 5. and 6., with four
different groups (a, b, c and d) attached to the central carbon atom (known as
the chiral carbon), 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 formula and
structural formula).
They only differ in their mirror image 3D spatial
arrangement of atoms and known as R/S isomers.
The central carbon atom of the Cabcd
molecule is described as an asymmetric carbon atom,
the centre of chirality or the chiral carbon
and the molecule exhibits chirality - so get used to
various overlapping terms!
They
are also known as enantiomers and optical isomers (explain later) because
R/S isomerism (R/S stereoisomerism) is originally known as
optical
isomerism.
The term R/S stereoisomerism is preferred these days, but lots of
'old' terms are still in general use!
Of course its much better to do the experiment with a
real 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.
The central carbon atom is described as asymmetric or
chiral.
This molecule exhibits R/S isomerism (optical
isomerism). ,
The two isomers (the R and S isomers (optical
isomers) are called enantiomers.- the two mirror image
forms.
This is another example of stereoisomerism - they have
identical structural formula, but differ in the spatial
arrangement of the atoms. |
 |
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) |
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and sub-indexes
Summing up the
properties 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).
The
non-superimposable mirror image isomers are called R/S (optical isomers)
also called 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 and the
molecule has chirality.
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 dotted line represents the mirror plane.
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.
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and sub-indexes
Measuring the
optical activity of R/S isomers (enantiomers) and
what is a racemate mixture?
This section follows on from the last sentence of the
previous section above:
The two R/S isomers have identical
physical properties such as melting point, solubility and density and
generally undergo the same chemical reactions in the same way and the
same rate - but that is not always the case e.g. in biochemical
reactions.
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.
Optical rotation of the
enantiomers is measured in a special polarimeter (usually aqueous)
solution tube:
The polarimeter is described further down this
section, but a few technical points first.
This feature of the solution of
the molecule known as optical
activity.
The plane of polarised light is rotated by a
solution of an asymmetric (chiral) molecule and the rotation maybe
clockwise or anticlockwise i.e.
+xo clockwise, dextrorotatory (D) or
-xo
anticlockwise, laevorotatory (L).
The D and L designation of optical isomers
(enantiomers) predates the IUPAC R/S system, but there is no change in the
+/- rotation notation!
Note that you cannot assume R and S go with + and -
or vice versa, because the IUPAC R/S isomer notation depends
on absolute priority rules for the a-d groups bonded to the
chiral carbon.
See
IUPAC
nomenclature R/S designation for configurations of
R/S enantiomers
A racemic mixture
(racemate) consists of an equimolar mixture of both
enantiomers
(usually in solution)
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 a racemate solution
does not contain optically active molecules, but you can say its
optically inactive.
Measurement of the rotation of
plane polarised light by chiral molecules
A polarimeter is an
instrument for measuring the rotation of plane polarised light by a
solution containing an optically active compound (diagram above
adapted from Wikipedia).
1. and 2. The monochromatic
light source, e.g. the intense yellow-orange light from a sodium lamp,
the electromagnetic radiation is oscillating/vibrating through
360o.
3. and 4. The light
passes through special a polarising filter e.g. Nicol prism to
produce polarised light that is only vibrating through a
narrow angle (a vertical plane in terms of the apparatus
diagram), this is now a plane polarised light beam.
5. This means the electromagnetic
oscillations
occur in a narrow plane instead of through 360o when
passing through the solution of the material under
investigation.
6. If the solution in the
polarimeter tube contains an optically active molecule
that is NOT a racemic mixture, the plane of the
polarised light is turned through a specific angle, which
can be clockwise (in diagram) or anticlockwise.
The angle of rotation depends on the
absolute optical activity of the specific R/S isomer
(enantiomer) and its concentration in the solution.
A angle may depend on there being a mixture
of the enantiomers, and if it is a 50:50 mixture, no angle
of rotation is observed. However, this can be used
quantitatively to measure the ratio of R/S isomers in a
mixture.
7. After
passing through the solution, the light passes through a 2nd
polariser (e.g. a 2nd Nicol
prism) that acts as the analyser to enable measurement of the
angle of rotation - the measure of optical activity.
8. The eyepiece can be rotated to
measure the rotation angle produced by the solution of the
enantiomer(s), an optically inactive solution would not show any
rotation of the plane polarised light beam.
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!
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and sub-indexes
Chemical
consequences of R/S isomerism and how can we separate R/S isomers?
Chemically their properties are
identical unless there is some stereospecificity in the reaction,
e.g. the 3D requirements of a
substrate molecule 'docking' into an enzyme or a reaction between optical
isomers of different molecules.
Many of the subtleties of
enzyme-substrate interaction (key and lock mechanism) are due to the
behaviour of a particular optical isomer.
It is quite common in biochemistry for R/S
isomers to undergo different biochemical reactions or a
reaction occurs with one isomer and not the other.
Many drug molecules exist as R/S isomers which
can have different pharmacological activity.
The sorts of chemical differences that can arise are
discussed in 10 case studies of stereoisomerism in the last section
of this page.
Separating R/S optical isomers - separating the
enantiomers from a racemate mixture - resolution
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 thought he was only famous for the pasteurisation of
milk!
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and sub-indexes
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,
 ,
3 different alkyl groups and
a hydrogen attached to the chiral carbon.
3-methylpent-1-ene,
 ,
3 different hydrocarbon groups and a hydrogen attached to the
chiral carbon.
2-bromo-3-chlorobutane,  , 
has two chiral carbons, so there will be 4 R/S stereoisomers.
1,1,2-trichlorocyclohexane, 
has a chiral carbon (C of lower C-Cl), so there will be
2 R/S stereoisomers (pair of enantiomers)
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,
,
,
2-methoxybutane,
,
, 3-iodobutanone and
CH3COCH(C6H5)CH3
3-phenylbutan-2-one
3-aminohexane,
 ,
2-methylbutanal,
 ,
2-chloropropanoic acid,
 ,
2-methylbutanoic acid ,
 ,
2-aminopropanoic acid,
 or
the ionic zwitterion forms have the
same chiral centre (C of the CH-NH2 or CH-NH3+
group) 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 - they have no chiral
carbon atom.
The IUPAC nomenclature R/S designation for absolute configurations of
enantiomers (optical isomers)
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and sub-indexes
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.
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 this carbon atom that is
chiral.
All the alpha-amino acids obtained
from proteins are optically active except glycine (2-aminoethanoic acid, R
= H),.
2-aminoethanoic acid, H2NCH2COOH, because it
has no chiral/asymmetric carbon atom.
There are two hydrogen atoms on the 'alpha' carbon,
so cannot have a chiral alpha carbon atom.
All the other 'alpha' amino acids have 4 different groups
attached to the alpha carbon atom next to the carboxylic acid group.
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
RCH(+NH3)COO-
and
R/S isomers in the non-ionic molecular form (R = CH3
for alanine etc.) and the zwitterion mirror image forms
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 a laboratory synthesis!
Its difficult, but not
impossible, but uses 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.
See also for amino acids
Part 8.8
Amino acids, peptides, polypeptides and types
of proteins
and Part
6.13
Amino acids - molecular
structure, preparation and reactions - two functional group chemistries
TOP OF PAGE
and sub-indexes
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,.
See also for amino acids
Part 8.8
Amino acids, peptides, polypeptides and types
of proteins
and Part
6.13
Amino acids - molecular
structure, preparation and reactions - two functional group chemistries
TOP OF PAGE
and sub-indexes
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
nucleophilic addition of hydrogen
cyanide to ethanal
See
case
study 12 for a general description of
nucleophilic addition to aldehydes or ketones where the product
can exhibit R/S isomerism - where I've done more detailed
diagrams.
(2) CH3CH(OH)CN + 2H2O
+ H+
CH3CH(OH)COOH + NH4+
hydrolysed by refluxing with dilute
acid
For more details on reaction (2) see
addition reactions of aldehydes/ketones.
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and sub-indexes
Case study 4a
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 foetus
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.
Case study 4b. The need
for modern CHIRAL
SYNTHESIS in the pharmaceutical industry
(1) Chiral
auxiliary
synthesis:
The 'active' or 'interacting'
part of a
molecule is called pharmacophore
group and changing its nature and the associated 'molecular
architecture' around it, may improve or change its pharmacological
activity.
A pharmacophore is a group of atoms which confers pharmacological
activity on a molecule.
One way round the stereoisomer
problem encountered in the synthesis 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
- which is very difficult using conventional non stereospecific
chemistry.
X can actually be a transition metal complex.
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.
(2)
Chiral synthesis and isomer separation can also be achieved using
enzymes.
These biological catalysts act in a
stereospecific way and can be employed to produce the desired R
or S enantiomer.
This avoids the problem of having to separate
the R/S isomers.
Enzymes can also be used to separate the
enantiomers if the production of a racemic mixture is
unavoidable in the principal synthesis reactions.
(3)
Chiral pool synthesis
This synthesis technique uses a pool of
naturally occurring chiral molecules as part of a synthetic
route.
The chirality of the original molecule can yield
the desired R/S isomer.
Common chiral starter materials include, apart
from aminoethanoic acid (glycine) alpha amino acids with at
least one chiral centre and sugars which have multiple chiral
centres.
(4)
Combinational chemistry
This is not a strictly speaking a chiral
synthesis method, BUT can be very important as a pre-screening
exercise e.g. linked in with (3) chiral pool synthesis
What is combinational
chemistry and what can it
do?
Combinatorial chemistry
is a means of automatically synthesising a range of different chemical compounds
from ensembles called 'libraries' and the efficient screening of the
different molecular 'combinations' for desirable properties which
maybe materials with physically desirable properties or drugs with
particular advantageous pharmacological properties.
It is possible to rapidly, and automatically, synthesise lots
of variations from selected to reactants and then screen the products
for their pharmacological activity.
Pharmaceutical costs due to chemical stereospecificity!
Because the enantiomers can have different
pharmacological activities and many a synthesis of a chiral centred drug
produces a mixture of enantiomers, 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 which consist of a
racemic mixture of the enantiomers and many are still 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 plus the
increased use of chiral synthesis.
TOP OF PAGE
and sub-indexes
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.
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.
TOP OF PAGE
and sub-indexes
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 so there is no need for chiral synthesis!
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.
TOP OF PAGE
and sub-indexes
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.
TOP OF PAGE
and sub-indexes
Case study
11 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?)
TOP OF PAGE
and sub-indexes
12. Nucleophilic addition to aldehydes and ketones
The general mechanism for nucleophilic addition
to an aldehyde or ketone, and illustrated here where the
electron pair donating nucleophile is the cyanide ion
to produce a hydroxynitrile compound.
A closer look at the initial attack of the electron
pair donating nucleophile on the carbonyl group carbon atom.
In this nucleophilic
addition reaction, at the functional group centre of the reaction
(>C=O), you change from an unsaturated trigonal planar situation to a
saturated tetrahedral bond network about the carbon atom. This carbon
atom is, in most cases a chiral carbon and the product therefore can
exhibit optical isomerism (R/S isomerism). However the product is usually a 50:50 mixture of the
enantiomers (non–superimposable mirror–image forms) i.e. a racemic mixture.
This discussion only applies if the nucleophilic
addition product has a
chiral carbon i.e.
has R/S isomers.
Why is the product an
optically inactive racemate even if the product is an asymmetric
molecule with a chiral carbon and hence exhibits R/S isomerism.
The reason can be clearly
argued by considering the mechanism 7
and the two other diagrams
above.
The nucleophile attacks the carbon of the polarised carbonyl
group (R2Cδ+=Oδ–)
in a trigonal planar bonding situation which changes to a tetrahedral on
formation of the C–Nucleophile bond.
Quite simply, there is a 50:50
chance of which side of the carbonyl group the nucleophile attacks and
therefore a 50:50 chance of which R/S optical isomer is formed as the
configuration about the carbon atom changes.
Examples where you do or do not get a racemic
mixture of R/S isomers
Nucleophilic addition of hydrogen cyanide to
propanal: DO
CH3CH2CHO
+ HCN ===> CH3CH2CH(OH)CN
The product is 2-hydroxybutanenitrile and
the chiral carbon atom is
highlighted.
Nucleophilic addition of hydrogen cyanide to
propanone: DO NOT
 CH3COCH3
+ HCN ===> CH3C(OH)(CN)CH3
The product is
2-hydroxy-2-methylpropanenitrile and has NO chiral carbon
atom because propane is a symmetrical ketone (R = R' in
terms of diagrams above).
TOP OF PAGE
and sub-indexes
13.
Stereochemistry of SN2 bimolecular nucleophilic substitution
I've discussed the nucleophilic substitution
reaction of hydroxide ion on two separate pages.
A general page on the reaction
of sodium hydroxide with halogenoalkanes
and the
mechanism and
stereochemistry of SN2 nucleophilic substitution
reactions
14.
Quantitative examples of using polarimeter to measure concentrations
including kinetic investigations
(a) The
hydrolysis of sucrose to glucose and fructose
All sugar molecules contain at least one chiral
carbon and their aqueous solutions usually exhibit optical
activity.
The reaction is:
C12H22O11
+ H2O ===> C6H12O6
+ C6H12O6
Sucrose solution rotates plane polarised light
in one direction and the mixture of glucose and sucrose in the
opposite direction.
Therefore you can follow the rate of the
reaction by using the angle of rotation as a relative measure of
the concentration of sucrose as it changes through the course of
the reaction.
(b)
Measuring the purity of an enantiomer (specific R/S isomer)
If you know the optical activity of the solution
of a pure sample of a specific enantiomer for a specific
concentration, you then have a benchmark for analysis.
e.g. you can compare the angle of rotation
(optical activity) of another solution of the same
enantiomer which might be contaminated with the other
enantiomer or a different optically active molecule to check
on the purity of the sample.
If the sample contains some of the other R/S
isomer enantiomer, it will reduce the angle of rotation in
the opposite direction and you can then calculate the ration
of the two R/S isomers in solution.
(c) The SN1
hydrolysis of an enantiomer of a halogenoalkane
e.g. tertiary halogenoalkanes hydrolyse with
sodium hydroxide via a carbocation mechanism (SN1).
If you start with a solution of a pure
enantiomer, you can follow the concentration decrease as it
hydrolyses by measuring the decrease in optical rotation with
time.
On completion the optical activity is
zero because a racemic mixture is formed.
RR'R"C-X + OH-
===> RR'R"C-OH + X-
(X = halogen Cl, Br or I, R, R' and R" =
H, alkyl or aryl, but all three must be different groups)
Why is a racemic mixture formed?
This is because a carbocation is formed
by heterolytic bond fission,.
The carbocation has a trigonal planar bond arrangement around the
positive carbon atom which can be attacked on either side on
a 50 : 50 basis by the hydroxide ion (mechanism and diagram
below).
Step 1.:
RR'R"C-X
===> RR'R"C+
+ X-
Step 2. :
RR'R"C+
+ OH- ===> RR'R"C-OH
Therefore if the product is also an
enantiomer, it is formed on a 50 : 50 ratio for the R : S
isomers.
TOP OF PAGE
and sub-indexes
15. Relatively simple molecules
with more than one chiral centre
(a)
2,3-dihydroxybutanedioc acid
 2-hydroxybutanedioic acid (malic acid),
only has one chiral carbon (2nd from the left) and can only
exist as only two enantiomers.
Indicated as the + and -
forms in terms of rotation of plane polarised light.
 However,
2,3-dihydroxybutanedioic acid (tartaric acid) has
two chiral carbons.
So how many stereoisomers will the
molecule have? The answer is 3.
If you think of + and - rotation there are 4
permutations, but two are the same i.e. for the two carbon atom
centres of chirality you can have
(+) (+),
(-) (-),
(+) (-) and
(-) (+),
but the last two permutations are identical because of the plane
of symmetry through the centre of the molecule.
Technically in terms of optical rotation and
absolute configuration they are denoted as:
(+)-R,R,
(-)-S,S and
meso.
That is two are +/- optically active forms and the meso form is
optically inactive - the optical effects of the chiral centres
cancel each other out.
(b) A
dipeptide molecule
Below is a diagram of a dipeptide molecule
composed of two amino acid residues of the alpha amino acids
phenylalanine and aspartic acid.
The original amino acids had one chiral centre
(asymmetric carbon atom), but the non-symmetrical dipeptide will
have two chiral centres.
Unlike example (b) where the molecule had a
plane of symmetry, no such plane exists here, so each chiral
centre results in two R/S isomers, giving a total of four R/S
stereoisomers.
If you think of + and - rotation there are 4
permutations, you can have
(+) (+),
(-) (-),
(+) (-) and
(-) (+),
and all of these permutation are different because there is no plane
of symmetry through the centre of the molecule.
The dipeptide shown is denoted by abbreviation
as Phe-Asp, but you can also have the dipeptide Asp-Phe which is
NOT the same molecule, which means there are another four
possible R/S stereoisomers.
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
Need to explain more on amino acids?
TOP OF PAGE
and sub-indexes
Diastereomers (in case you come across the terms):
Diastereomers
(diastereoisomers) are a type of a
stereoisomer.
Diastereomers are defined
as non-mirror image non-identical stereoisomers
Diastereomerism occurs when two or more stereoisomers
of a compound have different configurations at one or more of the
equivalent stereocenters BUT are NOT mirror images of each other.
E/Z isomers are examples of
diastereoisomers, and, as you will see, they are NOT mirror images
of each other (BUT R/S isomerism does
involve non-superimposable mirror image molecules.
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