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Basics of Stereochemistry
- 1. Prepared By Dr. Krishnaswamy.G Faculty DOS & R in Organic Chemistry Tumkur University Tumakuru For I M.Sc., I Semester DOS & R in Organic Chemistry Tumkur University Tumakuru Stereochemistry
- 2. Do the compoundshave same molecular formula? NO YES ISOMERS Do the compounds have same connectivity STEREOISOMERS (Do the compound be converted by rotation about C-C bond) CONSTITUTION ISOMERS (Do the compounds have different) NOT ISOMERS Functional group isomers Positional isomers Skeleton isomers Metamers NO YES Conformational isomers Configurational isomers (Isomers due to restricted rotation) NO YES Geometrical isomers Optical isomers (Are compounds are non super imposable mirror images) YES NO Diastereomers Enantiomers O H O Propanone Propanal OH OH 2-Propanol 1-Propanol Iso-butane n-butane O O Diethyl ether Methylpropyl ether YES NO E Z
- 3. Christian Huygens (1629-1695)discovered plane polarized light. Jean Baptiste Biot in 1815 noted that certain natural organic compounds rotate plane polarized light.
- 4. Louis Pasteur in1847 carried out crystallization of sodium ammonium salt tartaric acid and separated mirror image crystals by hand. The equimolar solution of separated crystals have equal but opposite optical activity. In 1847 Joseph A Lebel and Jacobs H Van’t Hoff proposed carbon with four attachment is tetrahedral and showed that carbon with four different attachments may exists as a pair of isomers.
- 5. Thalidomide disaster showedsignificance of stereochemistry. This drug was used to treat morning sickness in pregnant women. However, drug caused deformation in babies. It was found that one isomer was safe but other had tetratogenic (agent that disturb development of embryo) effect causing serious genetic damage. R-(+)-Thalidomide Acts as Sedative S-(-)-Thalidomide Acts as Tetratogenic Significance of Stereochemistry
- 6. It is branchof chemistry that involves the study of the different spatial orientation or arrangement of atoms or groups in the molecule. This branch of chemistry is commonly referred to as 3-Dimensional chemistry. Since, it focuses on stereoisomers (i.e. chemical compounds with same molecular formula but different spatial arrangement in three dimensions). What is Stereochemistry? Three terms are used to designate a carbon atom bonded tetrahedrally to four different substituents in a chiral molecule. (a) Asymmetric atom (LeBell & Vant Hoff) (b) Chiral centre (c) Stereocentre
- 7. Optical activity -the ability of chiral substances to rotate the plane of polarized light by a specific angle Racemic mixture - an equimolar (1:1) pair of enantiomers is called a racemic mixture. A racemic mixture has an optical rotation of zero. Scalemic mixture - Any unequal molar pair of enantiomers or non-racemic chiral substance is called Scalemic. Dextrorotatory (+): an optically active compound that rotates plane polarized light in a clockwise direction. Levorotatory (-): an optically active compound that rotates plane polarized light in a counter clockwise direction. Device used to measure optical rotation: Polarimeter Terminologies
- 8. The specific rotationof a compound is calculated using the following formula: Molecules with one stereocenter can be R or S = 2 possible stereoisomers. Molecules with n stereocenters can have all the possible combination of R and S for each stereocenter = 2n possible stereoisomers.
- 9. Essential criteria fora molecule to be chiral Criteria – 1: The carbon in the molecule should be attacked to four different groups. Criteria – 2: There must be lack of element of symmetry Improper Axis Symmetry (Sn) Plane of Symmetry (σ) Center of Symmetry (i)
- 10. (1) Proper Axisof Symmetry (Cn) (2) Improper Axis Symmetry (Sn) (3) Plane of Symmetry (σ) (4) Center of Symmetry (i) (5) Identity Element (E) Elements of symmetry The super-imposability of a molecule can be inspected conveniently by the following five elements of symmetry. CHIRAL
- 11. Identity Element (E) Doingnothing to the molecule is called Identity element.
- 12. Proper Axis ofSymmetry (Cn) An imaginary line passing through the molecule in such a way that when the molecule is rotated about it by an angle of 360o / n, an indistinguishable arrangement obtained. Such an axis is called Proper axis of symmetry. A molecule with Proper Axis of symmetry is chiral.
- 13. Plane of Symmetry(σ) A plane of symmetry is defined as an imaginary plane which divides a molecule in such a way that one half is mirror image of the other half. A molecule with atleast one plane of symmetry can be superimposed on its mirror image and is achiral.
- 14. Center of Symmetry(i) A Center of symmetry (Center of inversion) is defined as a point within the molecule such that if an atom is joined to it by a straight line which if extrapolated to an equal distance in opposite direction meets an equivalent atom. A molecule with atleast one Center of symmetry is achiral.
- 15.
- 16. Representation of threedimensional molecules (1) Dashed Wedge or Flying Wedge formula (2) Fischer projection (3) Sawhorse formula (4) Newmann projection Assigning configuration of a chiral molecule in three dimensional structure is not very easy to depict on a paper having only two dimensions. To overcome this problem four 2-dimesional structure s known as projections have been used.
- 17. (1) Dashed Wedgeor Flying Wedge formula In this representation a solid continuous lines represent bond is in the plane A solid wedge line represent bond is above the plane i.e. towards the observer A broken wedge / dashed line represent the bond is below the plane i.e. away from the observer ) ) In Plane Towards Observer Away from Observer
- 18.
- 19. (2) Fischer projection Inthis representation, bonds are drawn as solid lines. The bonds are placed vertical and horizontal to each other. Vertical bond Horizontal bond Asymmetric / Stereocenter
- 20. Horizontal line iscoming out of the plane of the page (towards observer) and Vertical line is going back behind the plane of the paper (away from observer) Away from Observer Towards Observer
- 21. In Fischer representation Mostoxidized carbon atom is placed on the vertical line at the top COOH CH3 NH2 H D-Alanine Most oxidize carbon COOH CH3 NH2 H D-Alanine
- 22. Disadvantage These projections canbe turned or rotated only in certain specified way. In compounds more than one stereocenters, a Fischer projection implies an eclipsing relationship of groups attached to two stereo centers but staggered is more stable than eclipsed.
- 23.
- 24. (3) Saw-horse representation Inthis representation each carbon atoms may be viewed as a letter “Y” CHO OH H CH2OH H Cl Front carbon Rear carbon H Cl CH2OH H OH CHO
- 25. CHO OH H CH2OH H Cl 1 2 3 4 4 3 2 1CH2OH CHO 4 3 2 1 Cl CH2OH H OH CHO 4 3 2 1 H Cl CH2OH 4 3 2 1 H CHO HO H Eclipsed Staggered Fischer projection Sawhorse projection Rotate C-2 by 180o
- 26. (4) Newmann Projections Inthis representation the molecule is viewed along the bond joining the two carbon atoms The front carbon shown by three solid lines i.e. “Y” The rear carbon is shown by a circle with three bonds pointing out from it i.e.
- 27. Combining the frontand rear results in the eclipsed Newmann projection which on rotation through 180o results in stable staggered Newmann projection Staggered Eclipsed Newmann projection
- 28. Propane staggered Newmannprojection from two views is shown below
- 29. Dashed Wedge FischerProjection Saw Horse Newmann SUMMARY
- 30.
- 33. H Br H OH H Br H OH HBr H OH Br H H OH Dash Wedge Fischer Saw Horse Newmann (3S, 4R)-4-Bromohexan-3-ol OH Br
- 34. INTER CONVERSION OFREPRESENTATIONS Conversion of Dash Wedge formula to Fischer projection Method-1: By viewing the molecule in between dash line and wedge line one can convert Dash formula to Fischer projection
- 36. If the solidlines are on right side in the first step solid line is written vertical. In the second step horizontal line is drawn and substituent present on wedge bond will be placed on right side. CH3 CHO Br H Right side CH3 CHO CH3 CHO H Br Step-1 Step-2 Method-2: To see whether the solid continuous line is left or right side
- 37. CH3 CHO Br H Right side CH3 CHO CH3 CHO H Br Step-1Step-2 CH3 CHO H Br Rotate 180o in the plane of the paper Most oxidised carbon in bottom Finally look for whether the most oxidized carbon is placed on top of the vertical line. If not rotate the Fischer projection through 180o in the plane of the paper.
- 38. If the solidlines are on left side in the first step solid line is written vertical line. In the second step horizontal line is drawn and substituent which is placed on wedge bond will be placed on left side. COOH H Left side COOH NH2 COOH NH2 CH3 H Step-1 Step-2 H2N CH3 Most oxidised carbon in top
- 40. Conversion of Fischerprojection to Dash Wedge formula In this conversion first step is Fischer vertical line will be written in solid line of Dash formula. In the second step horizontal line will be written in dashed line and wedge line. To place the substituent on dash and wedge line configuration of Fischer projection is used. Left side COOH NH2 CH3 H Step-1 COOH H2N Step-2 COOH H H2N CH3 (S)-Alanine (S)-Alanine COOH NH2 (S)-Alanine COOH NH2 H H3C Step-1 Step-2 Right side
- 41.
- 42.
- 43. Conversion of Fischerprojection to Newmann projection to Sawhorse formula Fischer projection is viewed either from front carbon or rear cabon atom which results in eclipsed Newmann projection. CH3 CH3 NH2 HO H Cl CH3 Cl H HO NH2 CH3 View through carbon attached to NH2, OH & CH3 Eclipsed
- 44. Rotation of eitherfront carbon or rear carbon 180o gives staggered Newmann projection. CH3 Cl H HO NH2 CH3 Eclipsed Cl H CH3 HO NH2 CH3 Staggered Newmann Projection Rotate rear carbon attached to Cl, H & CH3
- 45. Cl H CH3 HO NH2 CH3 CH3 CH3 NH2 HO Cl H View fromside Staggered Newmann Projection Staggered Sawhorse Projection
- 47. Conversion of Sawhorseformula to Newmann projection to Fischer projection Staggered Sawhorse formula is viewed either from front carbon or rear cabon atom which results in staggered Newmann projection. Rotation of either front carbon or rear carbon 180o gives eclipsed Newmann projection. This Newmann projection holding in vertical plane results in Fischer projection.
- 49. Conversion of Sawhorseformula to Fischer projection Staggered Sawhorse formula is converted into eclipsed projection by rotating either front carbon or rear carbon 180o. It is then held in vertical plane in such manner that the two groups pointing upwords are shown on the vertical line results in Fischer projection.
- 51. Three dimensional arrangementsof atoms or groups around an asymmetric carbon atom or chiral centre are known as configuration. Configuration
- 52. Two systems havebeen developed to study the configuration of organic compounds Relative configuration D-L configuration Cis-Trans configuration Configuration relative to that of standard ((+)-Glyceraldehyde) were determined. This system of configuration is known as D-L configuration. Configuration relative to that of substituents were determined. This system of configuration is known as Cis-Trans configuration. CHO CH2OH OH H H CH2OH HO CHO D-Glyceraldehyde L-Glyceraldehyde OH CH3 OH CH3 Cis Trans
- 53. Absolute configuration Due tosome draw backs of D-L configuration a new system called R-S system of configuration was developed by Robert. S. Cahn (Royal Institute of Chemistry, London), Christopher K. Ingold (University College, London) and Vladimir Prelog (Swiss Federal Institute of Technology, Zurich) in the 1950's, and is thus called the Cahn-Ingold- Prelog convention. OH CH3 OH CH3 Cis Trans (1R, 2S) (1S, 2S) Absolute configuration Relative configuration
- 54. D-L configuration D-L systemis seldom used today except for some class of compounds like carbohydrates and amino acids. D- & L - Glyceraldehyde are used as standard references for D-L system of configuration of carbohydrates. D- & L - Alanine are used as standard reference for alpha amino acid with D-L system of configuration.
- 55. D-series of sugarsare those with –OH group attached to highest numbered stereo center on the right side in Fischer projection.
- 56. L-series of sugarsare those with –OH group attached to highest numbered stereo center on the left side in Fischer projection.
- 57. D- & L-configuration of α-amino acid refers to the configuration of the regardless of the number of asymmetric carbon in the molecule.
- 58. D- & L-configurations are not related to the optical rotation of sugars. The D- & L- system has the disadvantage of specifying configuration of only one stereocenter.
- 59. Threo and Erythrosystem A molecule with two adjacent stereocenters and with two groups are common to each carbon while third group is different i.e. Cabx-Caby gives rise to threo and erythro diastereomers. When similar groups are on the same side = Erythro
- 60. When similar groupsare on the opposite side = Threo
- 61. The term erythroand threo are generally applied only to those molecules which do not have symmetric ends. Instead Meso or (d, l) will be used.
- 62. R-S Configuration Sequence (CIP)Rule is the method whereby the four substituents on an asymmetric carbon may be assigned priorities 1, 2, 3 or 4 so that the absolute configuration R or S may be determined. Rule-1: Rank the groups or atoms boned to the asymmetric carbon in order of priority. Priorities depend on atomic number; the atom of higher atomic number is assigned higher priority Cl 17 I 53 S 16 H 1 Atomic Number
- 63. Cl 17 Br 35 C6 H 1 Atomic Number If two atoms are isotopes of same element, the atom of higher mass number has the higher priority. Br 35 C 6 H 1 Atomic Number D 1 Mass Number 2 1 3 T > 2 D 1 H > Isotopes of Hydrogen
- 64. Rule-2: If therelative priority of two groups can not be determined as above, then look for next atom, often it may be necessary to proceed atom by atom till a point of difference is obtained. C + C + H = 6 + 6 + 1 = 13 H C Cl C C CH3 H H3C H H CH3 1 2 3 4 Cl 17 C 6 H 1 Atomic Number C 6 Same atomic number. Hence, look for next atom to decide priority C + H + H = 6 + 1 + 1 = 8
- 65. C+ H +H = 6 + 1 + 1 = 8 C H2 C C H2 Br H C H3C CH3 CH3 C+ C + C = 6 + 6 + 6 = 18 C+ H + H = 6 + 1 + 1 = 8 C 6 C 6 H 1 Atomic Number C 6 Same atomic number. Hence, look for next atom to decide priority C+ C + H = 6 + 6 + 1 = 13 1 4 CH C C H2 Br H C H3C CH3 CH3 C+ H + H = 6 + 1 + 1 = 8 1 2 3 4 CH C C H2 Br H C H3C CH3 CH3
- 66. Rule-3: In thecase of double or triple bond, either atoms or groups are considered as duplicate or triplicate. C A C A A C C A C A A A C C Duplicate Triplicate 1 2 3 4 C H C C C H H2C CH3 H2C H C C C C C C C C H C C H C + C + C = 6 + 6 + 6 =18 C + C + H = 6 + 6 + 1 =13 H H
- 67. Rule-4: Orient themolecule so that the groups or atoms with lowest priority are directed away from the observer. Rule-5: Draw an arrow from the group or atom with highest priority to the group or atom with next priority (decreasing priority). If you trace a circular path from 1 to 2 to 3 and the path describes a clockwise rotation, then the center is called R (Latin: rectus means right). If the path shows a counter clockwise rotation, then the chiral center is called S (L.: sinister means left). High Priority Low Priority Low Priority High Priority R S Clock wise Counter Clock wise
- 68. Case-1: When thegroup or atom of lowest priority is on continuous solid line, one can look along C-lowest priority group bond. H CH3 I Br 4 1 2 3 View the molecule along C-H bond I Br CH3 H 1 2 3 4 R
- 69. If the fourthgroup is on the plane then do double interchange in such a way that the 4th group goes below the plane. OR H CH3 I Br 4 1 2 3 R I CH3 H Br 4 1 2 3 First interchange I Br H H3C 4 1 2 3 Second interchange
- 70. Case-2: When thegroup or atom of lowest priority is oriented towards the observer, one may rotate the molecule so that priority 4th group point back. 4 1 2 3 S 4 1 2 3 Rotate
- 71. OR If fourth groupis above the plane, then clock wise movement is “S” while counter clock wise movement is “R” High Priority Low Priority Low Priority High Priority S R Clock wise Counter Clock wise
- 72. Case-I: If the4th group is present on top or bottom of the vertical line in the Fischer projection. R-S nomenclature for Fischer projection High Priority Low Priority Low Priority High Priority R S Clock wise Counter Clock wise H NH2 H3C COOH 1 2 3 4 S NH2 H COOH 1 2 3 4 R
- 73. Case-II: If the4th group is present on left or right of the horizontal line in the Fischer projection. High Priority Low Priority Low Priority High Priority S R Clock wise Counter Clock wise COOH NH2 CH3 H 1 2 3 4 S Ph C2H5 OH H3C 1 2 3 4 R
- 74.
- 75. (a) 2R,3S (b)2S,3R (c)2S, 3S (d) 2R, 3R The absolute configuration of C2 and C3 in the following compound is
- 76. •The absolute configurationof (a) 2S, 3S (b) 2S, 3R (c) 2S, 3S (d) 2R, 3R
- 77. CH3 H3C H2N HO Cl H CH3 CH3 NH2 HO H Cl Assign absolute configurationfor Dash Wedge and Fischer Projection Formula. Verify it is proper interconversion
- 78. CHO CH2OH OH H H CH2OH HO CHO D-Glyceraldehyde L-Glyceraldehyde Assignabsolute configuration for Fischer Projection Formula.
- 79. Chirality is alsoobserved in compounds that lack a stereogenic carbon atom. •Quaternary ammonium salts R4 N R3 R1 R2 Cl R4 N Cl R2 R3 R1
- 80. •Phosphine oxides O P R3 R1 R2 O P R2 R3 R1 •Silicon containingcompounds R4 Si R3 R1 R2 R4 Si R2 R3 R1
- 81. •Sulfones due todifferent isotopes S CH3 O16 O18 H3C