Stereochemistry and conformations

1. Stereochemistry and conformations • Ref. Books: • Stereochemistry Conformation & Mechanism - P.S. Kalsi • Organic Chemistry - L.G. Wade • Organic Chemistry - I.L. Finar Vol. 2 • Stereochemistry of Carbon Compounds • - E.L. Eliel

2. Stereochemistry • The branch of chemistry that deals with spatial arrangements of atoms in molecules and the effects of these arrangements on the chemical and physical properties of substances. • Stereochemistry refers to the 3-dimensional properties and reactions of molecules. • Deals with: • Determination of the relative positions in space of atoms, group of atoms • Effects of positions of atoms on the properties

3. Do the compounds have the same molecular formula ? No Yes Isomers No isomers Do the compounds have the same connectivity ? No Yes Stereoisomers Can the compounds be Interconverted by rotation about single bond? No Yes Configurational

4. Configurational Is the isomerism at a tetrahedral central? No Yes Optical Are the compounds non-superimposable mirror image ? No Yes

5. Configuration : same bonding connectivity, different arrangement in space • To change the configuration, you must always cleave and form new covalent bonds Conformation : interconvertible by rotations about single bonds • Different conformations, can be made identical with a rotation of 180 about the central single bond.

6. Definitions • Stereoisomers – compounds with the same connectivity, different arrangement in space • Enantiomers – stereoisomers that are non-superimposiblemirror images; only properties that differ are direction (+ or -) of optical rotation • Diastereomers – stereoisomers that are not mirror images; different compounds with different physical properties • Optical activity – the ability to rotate the plane of plane –polarized light • Polarimeter – device that measures the optical rotation of the chiral compound

7. Stereoisomerism Occurs when compounds having the same structural formula show different spatial arrangements of atoms. Geometrical Isomerism Arises from restricted rotation about a C=C double bond. cannot be inter-converted at lower temperatures

8. H H COOH H C C C C H COOH H C H C 5 6 5 6 trans-cinnamic acid cis-cinnamic acid • This process of rotation is associated with high energy (271.7 kJ mol-1). Thus at ordinary temperatures, rotation about a double bond is prevented and hence compounds such as CH3CH =CHCH3 exist as isolable and stable geometrical isomers. H H H C H 3 C C C C H C H CH 3 CH 3 3 trans-but-2-ene cis-but-2-ene

9. Necessary and sufficient condition for geometric isomerism • Geometrical isomerism will not be possible if one of the unsaturated carbon atoms is bonded to two identical groups. • No two stereoisomers are possible for CH3HC=CH2, (CH3)2C=CH2 and Cl2C=CHCl. • Compounds existing in two stereo-isomeric forms are: where a b and c  d

10. Determination of the configuration of the geometric isomers Physical methods • Melting points and boiling points: • Trans isomer has a higher m.p. due to symmetrical packing. • Cisisomer has a higher b.p. due to higher dipole moment which cause stronger attractive forces.

11. (b) Solubility: Cis-isomers have higher solubilities. Maleic acid 79.0g/100ml at 293KFumaric acid 0.7g/100ml at 293K (c) Dipole moment: In general, cis isomers have the greater dipole moment.

12. (d) Spectroscopic data : • IR: Trans isomer is readily identified by the appearance of a characteristic band near 970-960 cm-1. No such band is observed in the spectrum of thecisisomer. • NMR: The protons in the two isomers have different coupling constants e.g. trans – vinyl protons have a larger value of the coupling constant than the cis-isomer, e.g. cis- and trans-cinnamic acids.

13. E/Z notation If there are three or four different groups attached to the Cs of C=C double bond E/Znotation rather than the trans/cis notation is used to name the stereoisomers of a molecule. E : in opposition to  trans Z : together  cis     Z E This method, which is called the E and Z system, is based on a priority system originally developed by Cahn, Ingold and Prelog for use with optically active substance

14. 2 2 Br Br 1 Cl 2 F C C C C F 2 1 I 1 I 1 Cl E-1-Bromo-2-chloro- Z-1-Bromo-2-chloro- 2-fluoro-1-iodoethene 2-fluoro-1-iodoethene 1 1 H C H C 2 3 3 H CH 1 3 C C C C H 2 H 2 H 2 CH 1 3 E-2-Butene Z-2-Butene HOOC 1 1 H 2 COOH 1 COOH C C C C 2 H H 2 H 2 1 HOOC E-But-2-ene-1,4-dioic acid Z-But-2-ene-1,4-dioic acid (Fumaric acid) (Maleic acid)

15. Number of geometrical isomer of compounds containing two or more double bonds with non-equivalent terminii • Dienes in which the two termini are different (i.e. XHC=CH–CH=CHY), has four geometrical isomers . H H H H X X X X C C C C C C H C H C H H H H C C C H C H C C C C H Y H Y Y H Y H Z,Z, or cis-cis Z,E, or E,E or cis-trans trans-trans It means the number of geometrical isomers is 2n where n is the number of double bonds. E,Z or trans-cis

16. Geometric isomerism of oximes • The carbon and nitrogen atoms of oximes are sp2-hybridized, as in alkenes. • They should also exhibit geometric isomerism if groups R1 and R2 are different. • Beckmann (1889) observed that benzaldoxime existed in two isomeric forms and Hantzsh and Werner (1890) suggested that these oximes exist as the following two geometric isomers (I and II). • For fixing priority the lone pair of electrons on nitrogen is taken as group of lowest priority. or

17. Nomenclature of aldoximes • The prefixes synand antiare used in different context for aldoximes and ketoximes • In case of aldoximes, thesynformistheone in whichboththehydrogen and thehydroxyl (-OH) group are onthesameside of the C=N. Whereas in the anti form, they are ontheoppositeside. OH H H C N C N OH H C H C 5 6 5 6 -benzaldoxime syn -benzaldoxime anti

18. Nomenclature of ketoximes • In case of ketoximes, the syn and anti descriptor indicate the spatial relationship between the first group cited in the name and the hydroxyl group syn-ethylmethylketoxime syn-methylethylketoxime or or anti-methyethylketoxime anti-ethylmethyketoxime

19. The system of E-Z nomenclature has also been adopted for oximes. • For fixing priority the lone pair of the electrons on nitrogen is taken as group of lowest priority. Z-Methylphenylketoxime E-Methylphenylketoxime (1) (1) H C H C (2) (2) CH 5 6 5 6 H C H CH 3 H 3 H C 3 3 C C C C N N N N (2) (1) (2) (1) HO OH HO OH Z-Acetaldoxime E-Acetaldoxime

20. Chiral Carbons • Carbons with four different groups attached are chiral. • It’s mirror image will be a different compound (enantiomer).

21. Achiral Compounds Take this mirror image and try to superimpose it on the one to the left matching all the atoms. Everything will match. When the images can be superimposed the compound is achiral.

22. Chirality - optical activity: discovery • French chemist Louis Pasteur (1848) discovered that crystalline optically inactive sodium ammonium tartarate was a mixture of two types of crystals which were mirror images of each other. • Each type of crystals when dissolved in water was optically active. The specific rotations of the two solutions were exactly equal, but of opposite sign. • In all other properties, the two substances were identical. • As the rotation differs for the two samples in solution in which shapes of crystals disappear, Pasteur proposed that like the two sets of crystals, the molecules making up the crystals were themselves mirror - images of each other and the difference in rotation was due to 'molecular dissymmetry'

23. Chirality • An object which cannot be superimposed on its mirror-image is said to be chrial [Greek : Cheir 'Handedness'] and the property of non-superimposability is called chirality. Thus our hands are chiral. • The presence of a chiralitycentre usually leads to molecular chirality. Such a molecule has no plane of symmetry and exists as a pair of enantiomers. Such a carbon atom is sometimes also referred to as asymmetric carbon atom.

24. Asymmetric Carbons • The most common feature that leads to chirality in organic compounds is the presence of an asymmetric (or chiral) carbon atom. (A carbon atom that is bonded to four different groups) • In general: • no asymmetric C usually achiral • 1 asymmetric C always chiral • > 2 asymmetric C may or may not be chiral

25. Enantiomers • Enantiomers: stereoisomers that are non-superimposible mirror images Enantiomers (+) or (-)butan-2-ol • Mirror images of each other • Non-superimposable with each other

26. Fischer mirror images • The direction of optical rotation cannot be predicted from the structural formulae. • It can only be determined experimentally. • Easy to draw, easy to find enantiomers CH3 CH3 Cl H Cl H H Cl Cl H CH3 CH3 Enantiomers

27. Properties of enantiomers • Same boiling point, melting point, and density. • Same refractive index. • Rotate the plane of polarized light in the same magnitude, but in opposite directions. • Different interaction with other chiral molecules: • Active site of enzymes is selective for a specific enantiomer. • Taste buds and scent receptors are also chiral. Enantiomers may have different smells.

28. Stereochemistry • The properties of many drugs depends on their stereochemistry: (S)-ketamine (R)-ketamine anesthetic hallucinogen

29. Resolution of enantiomers • The process of separating enantiomers is called resolution. • Since enantiomers have identical physical properties, they cannot be separated by conventional methods. - Distillation and recrystallization fail. Methods of resolution: • Mechanical separation • Preferential crystallization • Resolution through the formation of diastereomers: chemical method • Biochemical method • chromatographic method

30. Resolution of enantiomers (chemical method) C(+) C(-) C(+)P(+) 2P(+) C(-)P(+) C(+)P(+) C(-)P(+) Separate diastereomers C(+) pure Enantiomers, racemic P(+) Add pure enantiomer P(+) C(-) pure

31. ()Tartaric acid (racemic mixture) + (-)cinchonidine (resolving agent) (+)tartaric acid  (-)cinchonidine Diastereomers (separable) + (-)tartaric acid  (-)cinchonidine dil. H2SO4 dil. H2SO4 (+)tartaric acid (crystalize out) (-)tartaric acid (crystalize out)

32. Biochemical Method Microorganisms or enzymes are highly stereoselective. • (+)-Glucose plays an important role in animal metabolism and fermentation, but (-)-glucose is not metabolized by animals, and furthermore cannot be fermented by yeasts. • Penicilliumglaucum, consumes only the (+)-enantiomer when fed with a mixture of equal quantities of (+)-and (-)-tartaric acids. • Hormonal activity of (-)-adrenaline is many times more than that of its enantiomer. • Limitations: • (i) These reactions are to be carried out in dilute solutions, so isolation of products becomes difficult. • (ii) There is loss of one enantiomer which is consumed by the microorganism. Hence only half of the compound is isolated (partially destructive method).

33. Chiral biological macromolecules • Proteins • Enzimes • Structural elements of membrances • Receptors • Carbohydrates • Nucleic acids • Chiral ‘building blocks’ of L-amino acids and D-carbohydrates

34. Biological discrimination of enantiomers • Enantiomers can be distinguished through the use of chiral probes. A polarimeter is one example of a chiral probe. • Enzymes are a type of chiral probe that are found in living systems. • In general, enantiomers do not interact identical with other chiral molecules • Enzymes are chiral, and are capable of distinguishing between enantiomers • Either one has no effect or has a totally different • Usually, only one enantiomers of a pair fits properly into the active site of an enzyme

35. Biological significance of chirality A schematic diagram of an enzyme surface capable of binding with (R)-glyceraldehyde but not with (S)-glyceraldehyde. Since most of the natural (biological) environment consists of enantiomeric molecules (amino acids, nucleosides, carbohydrates and phospholipids are chiral molecules), then enantiomers will display different properties. Then, in our body: R-glyceraldehyde S-glyceraldehyde This enantiomer of glyceraldehyde does not fit the same binding sites. This enantiomer of glyceraldehyde fits the three specific binding sites on the enzyme surface.

36. Discrimination of enantiomers Enzymes are capable of distinguishing between stereoisomers

37. Enantiomeric excess (ee): The excess of one enantiomer over the other in a mixture of enantiomers. Expressed mathematically:  enantiomeric excess = % of major enantiomer - % of minor enantiomer. Example: A mixture composed of 86% R enantiomer 14% S enantiomer ee of the mixture = 86% - 14% = 72% (excess of one over the other) d-l e.e = = X 100 X 100 (entire mixture) d+l

38. Optical Purity • Optical Purity : The optical purity is a measure of enantiomeric purity of a compound and is given in terms of its enantiomeric excess (ee). Optical purity is expressed as a percentage. • A pure enantiomer would have an optical purity and enantiomeric excess of 100%. • A fully racemised compound has 0% optical purity. • If the enantiomeric excess is 90%, means 90% pure enantiomer, remaining 10% contains equal amounts of each enantiomer (i.e. 5% + 5%). • Enantiomeric excess of a mixture of enantiomers is numerically equal to its optical purity.

39. Optical Purity • Optical purity (o.p.) is sometimes called enantiomeric excess (e.e.). • One enantiomer is present in greater amounts. observed rotation o.p. = Problem: The specific rotation of (S)-2-iodobutane is +15.90. Determine the % composition of a mixture of (R)- and (S)-2-iodobutane if the specific rotation of the mixture is -3.18. X 100 rotation of pure enantiomer 3.18 = 20% o.p. = X 100 15.90 l = ee + (100-20)/2 = 60% d = (100-20)/2 = 40%

40. Enantiomeric Excess (e.e.) Problem : When optically pure (R)-(-)-2-bromobutane is heated with water, 2-butanol is the product. Twice as much (S)-2-butanol forms as (R)-2-butanol. Find the e.e. and the observed rotation of the product. [α]=13.50° for pure (S)-2-butanol. Let consider x = amount of (R) enantiomer formed 2x = amount of (S) enantiomer formed observed rotation 33  13.50 o.p. = observed rotaion =  100 = 33% 100 rotation of pure enantiomer We know, e.e. = o.p. x 2x-x | d-l | = = e.e =  100  100  100 d+l 2x+x 3x = 4.5

41. Conformational mobility of cyclohexane Chair conformations readily interconvert, resulting in the exchange of axial and equatorial positions by a ring-flip

42. Substituted cyclohexanes Chirality of conformationally mobile systems Cis-1,2-dibromocyclohexane (1S,2R) • The planar diagram predicts achiral and optically inactive. • But we know the structure is not planar.

43. Chirality of conformationally mobile systems • This is a chiral structure and would be expected to be optically active cis-1,2-dibromocyclohexane Consider the chair interconversion….

44. Chirality of conformationally mobile systems cis-1,2-dibromocyclohexane SR(ax,eq) SR(eq,ax) • The two chair forms are enantiomers but not isolatable • Two structures have the same energy. Rapid interconversion. 50:50 mixture. Racemic mixture. optically inactive. • Planar structure predicted correctly

45. Trans 1,2 dibromocyclohexane • No mirror planes. Predicted to be chiral, optically active. trans-1,2-dibromocyclohexane (1S,2S) R,R (eq.eq) R,R (ax,ax) • Each structure is chiral. Not mirror images! Not the same! Present in different amounts. Optically active

46. Mobile conformers • If equilibrium exists between two chiral conformers, the molecule is not chiral. • Judge chirality by looking at the most symmetrical conformer. • Cyclohexane can be considered to be planar, on average.

48. Nonmobile conformers • The planar conformation of the biphenyl derivative is too sterically crowded. The compound has no rotation around the central C—C bond and thus it is conformationally locked. • The staggered conformations are chiral: They are nonsuperimposable mirror images.

49. Conformational Analysis • The different spatial arrangements that a molecule can adopt due to rotation about σ bonds are called conformations and hence conformational isomers or conformers.  • The study of the energy changes that occur during these rotations is called conformational analysis.

50. Structure of ethane