2. Stereoisomerism

Stereoisomerism  occurs when two or more compounds have the same molecular formula AND the same structural formula BUT differ in spatial arrangements of their bonds. There are two main sub-divisions of stereoisomerism, (a) Geometrical Isomerism and (b) Optical isomerism. A 3rd section (c), looks at other stereochemical examples which do not readily fit into (a) or (b)

(2a) Geometrical Isomerism (2b) Optical Isomerism (2c) Other organic stereoisomerism

2a Geometrical Isomerism

In these molecules spatially different isomers exist because of the inhibited/restricted rotation around at least one bond due to too high an energy requirement (don't say rotation is impossible!). The three most common situations you are likely to encounter are >C=C< or a >C=N- double bond and around a C-C single bond in cycloalkanes. In both cases the energy required is too high to allow free rotation BUT which is possible by e.g. the alkyl groups around the C-C single bonds in non-cyclo linear/branched alkanes.

If two identical atoms/groups are attached to the same carbon, you cannot have geometrical isomers e.g. those with R₂C=C< or R₂C=N- where R=R.

The nomenclature term cis often means the same substituents are on the same side of the double bond and trans when they are on opposite sides (there is a more sophisticated E/Z notation to cover all attached groups in a hierarchical way, but this is not dealt with here). NOTE: 

Case studies: 2a.1 C₄H₈ * 2a.2 HOOC-CH=CH-COOH * 2a.3 ClCH=CHCl

2a.4 di-substituted cycloalkanes * 2a.5 azo (-N=N-) and R₂C=N-X compounds

Case study 2a.1 Isomers of C₄H₈, cis/trans-but-2-ene

(1) cis (bpt 4^oC)   and (2) trans (bpt 1^oC)

(1) and (2) are very similar physically (e.g. colourless gases and very low bpt) and chemically (e.g. alkene electrophilic addition reactions).

Note that there are four other physically similar isomers of C₄H₈ namely, (3) 2-methylpropene (bpt -7^oC, chain isomer), (4) but-1-ene (bpt -6^oC, position of C=C isomer), (5) methylcyclopropane and (6) cyclobutane (bpts 5^oC and 13^oC, 5 and 6 are alkane functional group isomers of alkenes 1 to 4), BUT non of (3) to (6) can form geometrical isomers. (3) and (4) would be chemically similar to (1) and (2) being alkenes, but (5) and (6) have no 'alkene' chemistry but just the limited chemistry of alkanes e.g. uv chlorination as well as the combustion, which they all readily undergo!

Case study 2a.2 trans/cis-But-2-ene-1,4-dioic acid, HOOC-CH=CH-COOH

(butenedioic acids, old names given below).

On heating the trans form (1, Fumaric acid) it is difficult to change it into the cyclic anhydride (3) below.

cis form (2, Maleic acid) (3)  + H₂O

However, if the cis form (2) is heated, it readily changes into the cyclic acid anhydride (3). Not only does the restricted rotation about the C=C bond cause the existence of geometrical isomers, but in this case you can only readily get the elimination of water when the two -OH groups are on the same side of the planar >C=C< system, as in the cis form (2). In the trans form (1) the elimination reaction is stereochemically hindered because the -OH so far apart. However, both (1) and (2) undergo the same electrophilic addition reactions of the 'alkene' double bond, >C=C< and the same reactions of the carboxylic acid group -COOH.

Some physical differences.

*Sometimes the trans isomer has the higher symmetry and packs more closely into a crystal lattice, increasing the intermolecular forces, and this tends to increase melting points and density but decrease solubility as solvation is not as energetically favourable. (* unfortunately, there seem to be many exceptions to this 'rough rule of thumb', so beware).

(1) The trans form: d = 1.64 gcm^-3, solubility in water 0.7g/100 cm³ at 25 ^oC, melting point 287 ^oC, 

(2) The cis form: d = 1.59 gcm^-3, solubility in water 78.8g/100 cm³ at 25 ^oC, melting point 130 ^oC,

Case study 2a.3 Physical properties of cis/trans-1,2-dichloroethene

The C^d+-Cl^d- bond is polar due to the difference in electronegativity between carbon and chlorine (Cl > C).

(1) cis d = 1.265cm^-3, mpt -80 ^oC, bpt 60 ^oC, dipole moment 1.89_D, with both Cl's on the same side of the C=C bond, the combined effect of the two polar C-Cl bonds makes it a much more polar molecule and raises the bpt compared to (2), but not the mpt.

(2) trans   d = 1.259cm^-3, mpt -50 ^oC, bpt 48 ^oC, dipole moment 0.00_D, the effect of the C-Cl polar bonds cancel each other out giving a relatively non-polar molecule, this 

and there is positional isomer (3) shown below.

(3) d = 1.218 cm^-3, mpt -? ^oC, bpt 32 ^oC, dipole moment 1.30_D?, 1,1-dichloroethene, is a positional isomer of the two geometrical isomers and cannot exhibit geometrical isomerism because two identical groups (H's or Cl's) are attached to the same carbon of the double bond.

All three isomers are chemically similar e.g. the electrophilic addition reactions of alkenes.

Case study 2a.4 Di-substituted cycloalkanes

Cis and trans isomers can exist in 1,2-disubstituted cyclopropanes* and cyclobutanes* because the -C-C- ring structure inhibits rotation about the C-C bonds. If the 1,2-substituents are on the same side of the plane of the triangle/square of carbon atoms you get the cis form, if the are on opposite sides you get the trans form. * Alicyclic compounds (means cyclo-aliphatic)

(1) 1,2-dichlorocyclopropane can give ...

(2) (cis) and (3) (trans)

  to help think in 3D!

(4) 1,1-dichlorocyclopropane is a positional isomer of C₃H₄Cl₂, which cannot exhibit geometrical isomerism.

(5) 1,2-dibromocyclobutane, likewise can give ...

(6) (cis) and (7) (trans)

(8) or (9) 1,1-dibromocyclobutane, is a positional isomer of C₄H₆Br₂ and cannot exhibit geometrical isomerism because the two bromine atoms are attached to the same carbon.

(10) 1,3-dibromocyclobutane is also positional isomer of C₄H₆Br₂ and can exhibit geometrical isomerism.

(11) cis and (12) trans

Note: The molecular formulae C₃H₄Cl₂ and C₄H₆Br₂ can theoretically give rise to other functional group/positional/geometric isomers in the form of non-cyclic alkenes e.g. (13) ClCH₂CH=CHCl (1,3-dichloropropene) or (14) CH₃CHBr=CHBrCH₃ (2,3-dibromobut-2-ene) etc. etc!

Case study 2a.5 Isomerism in azo (-N=N-) and R₂C=N-X compounds

Organic (or inorganic) compounds of the structure R-N=N-R' (e.g. aromatic azo dyes) can exist as cis and trans isomers in just the same way as alkenes, where R or R' = H, alkyl, aryl group etc. R can be different or the same as R'. Stereochemically, the lone pairs on the nitrogen effectively behave as an atom bonding pair of electrons in determining the trigonal planar orientation of the -N= bonds and the lone pair of electrons on the nitrogen. Three groups of electrons around an atom X, always give a trigonal planar arrangement around the central atom >X-. The double bond, N=N or C=N, ensures that too high an energy is required for ready rotation about the double bond. The cis and trans forms will have different physical properties such as melting/boiling points.

Examples of -N=N- systems:

(1) (cis) and (2) (trans)  

(all R-N=N-R' bond angles are about 120^o)

Examples of >C=N- systems

Carbonyl compounds like aldehydes and ketones undergo condensation reactions of the type

RR'C=O + H₂N-X => RR'C=N-X + H₂O 

where R is different to R' and = H, alkyl or aryl etc. geometrical isomers can occur.

and when X= H (ammonia), alkyl (aliphatic primary amine), aryl (aromatic primary amine), OH (hydroxylamine), NH₂ (hydrazine), NHC₆H₃(NO₂)₂ (2,4-dinitrophenylhydrazine)

(3) (cis wrt R') and (4) (trans wrt R')  

(you can think of R' as a higher ranking group wrt R)

When R = R' i.e. (5) geometrical isomerism is not possible.

(all >C=N-X angles are about 120^o)

2b Optical Isomerism

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

2b.4 Thalidomide * 2b.5 nucleophilic substitution of halogenoalkanes * 2b.6 amino acids-proteins-enzymes

Introduction

When two compounds have the same molecular and structural formula BUT can have mirror image forms which are NOT superimposable on each other. The non-superimposable isomers are called optical isomers (or enantiomers). The organic molecule must possess an asymmetric or chiral carbon, to which four different groups are bound in a tetrahedral bond arrangement (shown as R, R', R'' and R''' in the diagram below). Chirality is the property of 'handedness' i.e. right and left hand, which are mirror images of each other but you can't have identical hands spatially in 3D! The R's can be H, alkyl, aryl, halogen, -COOH, -NH₂, etc. etc.! as long as the all four are different, optical isomers can exist!

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

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 360^o. 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).

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.

Case study 2b.1a Alpha amino-acids

Alpha amino acids like RCH(NH₂)COOH below, are classic examples from natural sources e.g. CH₃CH(NH₂)COOH, is called 2-aminopropanoic acid (the amino acid alanine, R = CH₃). The alpha means a '2-amino' carboxylic acids, i.e. the 1st carbon to which a substituent group like NH₂ can be attached.  CH₃CH(NH₂)CH₂COOH is 3-aminobutanoic acid, old name, beta amino-butyric acid, beta meaning on the 2nd possible carbon for a substituent group. All the alpha-amino acids obtained from proteins are optically active except glycine (R = H), 2-aminoethanoic acid, H₂NCH₂COOH, because it has no chiral/asymmetric carbon atom. In aqueous solution, and in the solid state, they predominantly exist as zwitterions, the ionic form derived from proton transfer from the carboxylic group onto the amino group.

RCH(NH₂)COOH RCH(⁺NH₃)COO^-

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 (enantiomers) and on extraction, purification and isolation, they show optical activity (that is rotating the plane of polarised light in a polarimeter tube). 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. It is wrong to say that optical isomers are not 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 2b.2 and 2b.3). However, since the 1990's the problem is being tackled by the use of chiral auxiliary molecules.

Case study 2b.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

chlorination of propanoic acid with chlorine/uv (also forms isomeric 3-chloropropanoic acid)

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

treating 2-chloropropanoic acid with excess conc. ammonia

In stage (1) the chlorine radical could abstract/substitute either of the two middle H's with equal probability OR if stage (2) went via a carbocation (with a trigonal planar bond arrangement), then either step could give an equimolar mixture of the possible optical isomers of 2-chloropropanoic acid OR 2-aminopropanoic acid.

Case study 2b.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

(2) CH₃CH(OH)CN + 2H₂O + H⁺ CH₃CH(OH)COOH + NH₄⁺  

hydrolysed by refluxing with dilute acid

Case study 2b.4 Thalidomide tragedy and some important concepts in drug design

adapted from http://webbook.nist.gov/chemistry/

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.

In the synthesis of pharmaceuticals it is highly desirable, if not easily achievable, to produce drugs of a chiral nature, containing only a 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 .

Combinational chemistry:

This was mentioned in case study 2b.6 for the laboratory synthesis of polypeptides and can also be applied to the synthesis of drugs. 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. It is possible to rapidly, and automatically, synthesise lots of variations from selected to reactants and then screen the products for their pharmacological activity.

* A pharmacophore is a group of atoms which confers pharmacological activity on a molecule.

Case study 2b.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 S_N2 mechanism prevails, that is a single step bimolecular collision of the reactants (without intermediate carbocation formation), a single optical isomer of the alcohol is formed. In fact the spatial orientation about the chiral carbon is inverted, as is the optical activity in terms of the direction plane polarised light is turned (e.g. a Dextro form becomes a Laevo form).

i.e. RR'R''^*C-X + OH^- ==> RR'R''^*C-OH + X^-

(b) If the S_N1 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 possible optical isomer. The two optically activities cancel each other out, so zero rotation of plane polarised light. 

For detailed discussions see the mechanisms part II page.

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

GENERAL REVISION NOTES

Revision notes for studying revising tutoring teaching Advanced Level GCE AS A2 CHEMISTRY courses in unofficial support the Chemistry in any advanced-subsidiary AQA, Edexcel, OCR, CIE, WJEC, SQA and CCEA (NI) UK or Cambridge/London/Edexcel International and OCR/CIE and International Baccalaureate (IB) examinations.

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