Isomerism organic chemistry topic ......

Geometrical isomerism

1. Isomerism Chapter 3 (Part 1)

2. Course Learning Outcomes On completion of this chapter, students will be able to understand: Understand what isomerism is and its significance in chemistry. Identify and represent stereoisomers using methods like wedge-hatched bonds, Fischer projections, sawhorse projections, and Newman projections. Identify and illustrate different conformations, including eclipse, staggered, gauche, and anti-conformation, in common organic molecules. Distinguish between configurational and conformational isomers. Understand the conditions and requirements for geometric isomerism

3. Presentation of Organic Compounds Compounds must be presentable Various presentation ways, subject to the information, eg. Structure Pentane Molecular Formula Empirical Formula Line bond Structures Condensed Structures Skeletal Structures Number of atoms of each element in one molecule of a compound C 5 H 12 Relative ratio’s of elements preset C 5 H 12 Show all atoms and bonds Show all atoms, but only show bonds when necessary Only C-C bonds C 6 H 12 O 6 Vs CH 2 O

4. Alkanes and Alkane Isomers Alkanes : Compounds with C-C single bonds and C-H bonds only (no functional groups) Connecting carbons can lead to large or small molecules The formula for an alkane with no rings in it must be C n H 2n+2, where the number of C’s is n Alkanes are saturated with hydrogen (no more can be added) They are also called aliphatic compounds

5. Isomerism Isomers : Compounds that have identical molecular formulas, but different arrangement of atoms Constitutional (Structural) isomers : Same formula, different arrangement Stereoisomers : Same formula, same arrangement, different 3D orientation E.g. Structural isomers of C 2 H 6 O. At room temperature: Ethyl alcohol is a liquid, completely soluble in water Dimethyl ether is a gas, partially soluble in water

6. Types of Isomerism

7. Stereochemistry Stereochemistry is also known as three-dimensional (3D) chemistry because the prefix “stereo-” means “three-dimensionality” Stereochemistry: study the arrangement of atoms in space in 3D structure and its effect on physical, chemical and biological properties In pharmaceuticals, slight differences in 3D spatial arrangement can make the difference between targeted treatment and undesired side effects. Why??

8. In pharmaceuticals, the 3D spatial arrangement of a molecule, known as its stereochemistry , is crucial because it determines how the drug interacts with biological targets, such as enzymes or receptors. Here's why slight differences in 3D structure can make a huge impact: Molecular Recognition : Many biological molecules are chiral, meaning they have a specific 3D shape. Receptors, enzymes, and other biological targets often bind to drugs like a "lock and key," where only the right 3D shape of the drug will fit properly. A different spatial arrangement might not fit as well or at all. Enantiomers and Chirality : Some drugs have enantiomers , which are molecules that are mirror images of each other but not superimposable, like left and right hands. These enantiomers can have very different effects in the body. For example, one enantiomer may produce the desired therapeutic effect, while the other might be inactive or even cause harmful side effects. Specific Binding : A drug's effectiveness depends on how specifically it can bind to its target in the body. A slight difference in the 3D structure might prevent the drug from binding to the correct receptor or enzyme, or it may bind to the wrong target, causing unintended side effects. Metabolism and Clearance : The body's enzymes that metabolize drugs are also stereospecific. Different 3D arrangements can affect how a drug is broken down, its duration of action, and how quickly it is cleared from the body. A famous example is thalidomide , where one enantiomer was effective in treating morning sickness, but its mirror image caused severe birth defects. This highlights the importance of stereochemistry in drug design and safety.

9. Stereochemistry S isomer is biologically active (S)-Ibuprofen is used primarily for fever R isomer is biologically inactive (R)-Ibuprofen R isomer is biologically active (R)-L-dopa is used for parkinson disease S isomer is biologically inactive (S)-L-dopa Maleic acid (Cis- butenedionic acid) Fumaric acid (Trans- butenedionic acid) R isomer is biologically active (R)-Salbutamol is bronchorelaxant S isomer is biologically inactive (S)-Salbutamol is bronchospasm

10. Constitutional Isomers Constitution/structural isomers have:

11. Stereoisomers Stereoisomers have: There are four main types of representations for open-chain molecules and are used to show the three-dimensional structure of chemical compounds

12. Wedge-hatched bond structure Wedge-hatched is usually done for molecules containing chiral center or chiral carbon (carbon atom that has four different substituents) Wedge (The bond in front of the plane) and Hatched (behind the plane) The bonds in the same plane draw in straight line, the bond in front of plane draw wedge while in behind the plane draw Hatched

13. Fisher projection Fisher projection: is a two-dimensional representation of a three-dimensional In Fisher projection: The horizontal line represent bond above the plane (front/wedge) and vertical lines represent bonds below the plane (back/Hatched) Fisher projections were originally proposed for the depiction of carbohydrates Two bonds are coming out of the plane. The two remaining bonds are going into the plane are on a vertical plane

14. Fisher projection Fisher projection is used to differentiate between L- and D- compounds

15. Sawhorse projection Sawhorse structure is used to show interactions between groups on adjacent carbon atoms

16. Sawhorse projection Sawhorse structure used for explain Conformational isomerism and explain rotation around single bonds (alkane) Eclipsed form less stable than staggered form due to torsional strain.

17. Newman projection Newman projection is used mainly for determining conformational relationship and to show interaction leading to steric hindrance between atoms or groups Steric hindrance : each atom occupies a certain amount of space when atoms are brought too close together leads high energy due to overlapping electrons clouds To write a Newman projection formula : We imagine ourselves taking a view from one atom (usually a carbon) directly along a selected bond axis to the next atom (also usually a carbon atom) The front carbon and its bonds are represented as The back carbon and its bonds are represented as

18. Conformational Isomers Isomers have different spatial orientations of atoms in a molecule that result from : Rotations about single bond (alkanes) Ring flipping conformations (cycloalkanes) The resulting arrangement referred to eclipsed and staggered conformers Rotation occur only in alkane (single bonds) not occur in alkene and alkyne

19. Conformational Isomerism in Alkanes (Ethane) Representing 3D conformers in 2D is done with standard types of drawings Molecular models are 3D objects that enable us to visualize conformers There are two representations: 1) Sawhorse representation 2) Newman projection

20. Conformational Isomerism in Alkanes (Ethane) Dihedral angle or Torsional angle ( ) (in degrees) : angle between the plane formed by the first three atoms and the plane formed but the last three atoms Rotation can be clockwise or anti-clockwise Sawhorse representation C-C bonds are at an angle to the edge of the page All C-H bonds are shown 2) Newman projection Bonds to front carbon are lines going to the center Bond to rear carbon are lines going to the edge of the circle

21. Conformational Isomerism in Alkanes (Ethane) When one of the carbon atom (front) is kept fixed and other is rotated about C-C bond an infinite numbers of isomers are possible by rotation about single bonds

22. Conformational Isomerism in Alkanes (Ethane) 30 30 Any conformations between eclipsed and staggered are called skew conformations Skew conformation of ethane is rapid at room temperature , and is sometimes described as free rotation Eclipsed form (highest energy), skewed form (intermediate energy), staggered (most stable)

23. Conformational Isomerism in Alkanes (Ethane) Potential energy changes that accompany rotation of group about the carbon-carbon bond of ethane The barrier to rotation between conformations is small (12 kJ/mol; 2.9 kcal/mol) The eclipsed conformers are 12 kJ/mol higher in energy than the staggered conformers – energy due to torsional strain Each H-H interaction contributes 4.0 kJ/mol

24. Draw Newman projection  Sawhorse projection

25. Conformational Isomerism in Alkanes (Propane) Propane (C 3 H 8 ) has torsional barrier around the carbon-carbon bonds (14 kJ/mol) Eclipsed conformer of C 3 H 8 has two ethane-type H-H interactions and an interaction between C-H and C-C bond The C-H and C-C bond interactions contributes 6.0 kJ/mol (=14 – (2 x 4.0))

26. Conformational Isomerism in Alkanes (Propane) Example: Make a graph of potential energy versus angle of bond rotation for propane, and assign values to the energy maxima

27. Conformational Isomerism in Alkanes (Propane) Example: Draw Newman projections of the most stable and least stable conformations of 1-bromopropane

28. Conformational Isomerism in Alkanes (Butane) As the alkane becomes larger, the conformations become more complex Butane has eclipsed and staggered conformers with different energy level around C2-C3: Syn (eclipsed) called fully eclipsed Eclipsed called partial eclipsed

29. Conformational Isomerism in Alkanes (Butane) Syn -eclipsed is the less stable , high energy conformers due torsional angle=0 ° which lead to high torsional strain and has high steric hindrance Anti-staggered is the most stable , lowest energy conformers due to the torsional angle = 180° which lead to low torsional strain and has less steric hindrance Torsional angle Torsional strain Stability

30. Conformational Isomerism in Alkanes (Butane)

31. Conformational Isomerism in Alkanes (Butane) Stability of all conformers of butane Syn Eclipsed (Fully Eclipsed) Torsional angle zero & Torsional strain maximum Has steric strain Staggered (Gauche) Torsional angle=60 ° Has steric strain More stable than fully eclipsed Eclipsed (Partial Eclipsed) Torsional strain = 120 ° & Torsional strain less than fully eclipsed More stable than fully eclipsed Anti-staggered Torsional angle = 180 & has lowest torsional strain More stable form

32. Conformational Isomerism in Alkanes (Butane)

33. Conformational Isomerism in Alkanes Example: For each of the following compounds, predict the energy barrier to rotation

34. Conformational Isomerism in Alkanes Example: For each of the following compounds, predict the energy barrier to rotation Answer: 6 kJ/ mol 6 kJ/ mol 6 kJ/ mol Total cost: 18 kJ/ mol 4 kJ/ mol 6 kJ/ mol 6 kJ/ mol Total cost: 16 kJ/ mol 4 kJ/ mol 4 kJ/ mol 4 kJ/ mol Total cost: 12 kJ/ mol 3.8 kJ/ mol Total cost: 3.8 kJ/ mol

35. Conformational Isomerism in Alkanes Example: Consider the following compound: Rotating only the C3-C4 bond, identify the lowest energy conformation Rotating only the C3-C4 bond, identify the highest energy conformation Answer:

36. Configurational vs. Conformational Isomers

37. Configurational Isomers Configurational isomers are stereoisomers that cannot be converted into one another rotation around a single bond

38. Geometrical Isomers Geometrical isomers: compounds with the same connectivity, different arrangement of atoms in space Two system used to describing the orientation of substituents within a molecule (configuration at double bond and configuration of cyclic compound) , known as cis/trans or E/Z system Substituents on the same side ( cis , latin word) or opposite side ( trans ) of double bond or ring When two groups are the same to use the cis/trans system of naming, if you have four different groups on a double bond use E/Z system

39. Geometrical Isomers The chemical properties of geometrical isomers tend to be similar but their physical properties are different E/Z isomers is used when there are more than two different substituents on a double bond Z (from the German zusammen ) means “together” and corresponds to the term cis E (from the German entgegen ) means “opposite” and corresponds to trans

40. Geometrical Isomers Rank the atoms directly attached to double bond according to their atomic numbers High priority is given to the atom with higher atomic number {H-(1) < C-(6) < N-(7) < O-(8) < F-(9) < Cl-(17) < Br-(35) < I-(53)} If isotopes of the same element are present, the higher priority is given to the isotope with higher atomic mass (mass number) Ordinary hydrogen is written 1H1 , deuterium is 2H1 , and tritium is 3H1

41. Nomenclature of Z/E isomers The E-Z nomenclature is proposed by three chemists Canh , Ingold and Prelog . Therefore rules based on it is called as C.I.P rules Rule No 01 : Atom directly attached with restricted atom if have higher atomic number than is has high priority for example

42. Nomenclature of Z/E isomers Rule No 02 : If directly attached atoms are same, then go to next atom and follow the same concept of higher atomic number for example

43. Nomenclature of Z/E isomers Rule No 03 : If groups have multiple bond then convert all π bonds into hypothetical sigma bonds and follow the same concept of higher atomic number

44. Nomenclature of Z/E isomers Rule No 04 : Only in case of isotopes higher atomic mass is given higher priority

45. Geometrical Isomers Exercise : Are these cis or trans ?

46. Geometrical Isomers Answer : Are these cis or trans ?

47. Geometrical Isomers Exercise : Name each, using cis-trans prefixes when needed?

48. Geometrical Isomers Answer : Name each, using cis-trans prefixes when needed?

49. Geometrical Isomers Exercise : Order the following in increasing priority ? -H, -Cl, -OH -CH 3 , -CH 2 OH, -CH 2 CH 3 -C=CH, -CH=CH 2 , -CH=O Answer -H, -OH, -Cl -CH 3 , -CH 2 CH 3, -CH 2 OH -C=CH, -CH=CH 2 , -CH=O

50. Geometrical Isomers Exercise : Determine if each of the following alkenes has and E or Z configuration? 4,4-dimethylpent-2-ene 4-ethyl-3-heptane 1-bromo-2-chloro-2-methylbut-1-ene Answer Z-1-bromo-2-chloro-2-methylbut-1-ene trans-4,4-dimethylpent-2-ene cis-4,4-dimethylpent-2-ene Cis/trans-4-ethyl-3-heptane

51. Properties of Geometrical Isomers The chemical properties of geometrical isomers tend to be similar but their physical properties are different

52. To be continued