Lecture 6 Stereochemistry PDF

1 Ass. Prof. Abeer Abdelazeem Mohamed  Pharmaceutical Organic Chemistry I (PC102- C) Ass. Prof. Abeer Abdelazeem 2 Ass. Prof. Abeer Abdelazeem Mohamed  Lecture 6...

1 Ass. Prof. Abeer Abdelazeem Mohamed  Pharmaceutical Organic Chemistry I (PC102- C) Ass. Prof. Abeer Abdelazeem 2 Ass. Prof. Abeer Abdelazeem Mohamed  Lecture 6 Course Learning Outcomes (CLOs) 1-1-1-1. Outline the basic concepts of stereochemistry, including isomerism and optical isomers, which can be utilized to prepare certain medicines. 2-2-1-2. Solve stereochemical problems to differentiate between optical isomers that may be used to prepare some medicines. References Organic Chemistry by Janice Gorzynski Smith, 6th edition, Publication: Mc Grow Hill Education, 2020. 3 Ass. Prof. Abeer Abdelazeem Mohamed  Stereochemistry  Stereochemistry is also known as three-dimensional (3D) chemistry as the prefix "stereo- " means "three-dimensional ".  Stereochemistry is the study of the arrangement of atoms in Space and its effect on physical, chemical, and biological properties. 4 Ass. Prof. Abeer Abdelazeem Mohamed  Isomerism 5 Ass. Prof. Abeer Abdelazeem Mohamed  Isomerism Isomers are compounds with the same molecular formula, but different structures. They are not identical They fall into two main classes. Stereoisomers (configurational Constitutional (structural) isomers isomers) differ in how their atoms are arranged in space. differ in the way their atoms are connected. Stereoisomers are different compounds that do not readily interconvert. 6 Ass. Prof. Abeer Abdelazeem Mohamed  Chirality superimposable Objects that are not chiral are said to Objects are chiral if they have a non-superimposable be achiral. An achiral object has a mirror image. superimposable mirror image. 7 Ass. Prof. Abeer Abdelazeem Mohamed  Chirality Objects are not the only things that can be chiral. Molecules can be chiral too. The usual cause of chirality in a molecule is an asymmetric center.  When sp3 hybridized, tetrahedral carbon is attached to four different groups. The molecule cannot be superimposed on its mirror image, which is said to be Chiral.  These Compounds are free from elements of symmetry.  Molecules such as CC14, and CH2Cl2 that can be superimposed on their mirror images are said to be ‘achiral’. 8 Ass. Prof. Abeer Abdelazeem Mohamed  Chirality Molecules are chiral if they have a non-superimposable mirror image. 9 Ass. Prof. Abeer Abdelazeem Mohamed  Elements of symmetry A symmetry element is a line, plane, or point through an object, where a rotation or reflection results in an orientation indistinguishable from the original. Achiral compounds contain one of the elements of symmetry such as: a) Plane of symmetry SP3Carbon attached to at least 2 similar groups Mirror plane Achiral Achiral 10 Ass. Prof. Abeer Abdelazeem Mohamed  Chirality Classify each of the following compounds as chiral or achiral and if chiral indicate the chiral carbon. * Chiral Achiral Achiral * * Achiral Chiral Chiral 11 Ass. Prof. Abeer Abdelazeem Mohamed  Chirality Identify each asymmetric carbon atom in the following structure * * * - Only three sp3 carbons are asymmetric 12 Ass. Prof. Abeer Abdelazeem Mohamed  Chirality Tetracycline is a broad-spectrum antibiotic because it is active against a wide range of bacteria. How many chiral centers/asymmetric centers does tetracycline have? Key answer - Only sp3 carbons can be asymmetric centers. - Only sp3 carbons bonded to four different groups. - Locate all the sp3 carbons - Then determine the sp3 carbons attached to four different groups - Tetracycline has nine sp3 carbons - Only five sp3 carbons are asymmetric which are 3,4,6,7 & 9. 13 Ass. Prof. Abeer Abdelazeem Mohamed  Chirality How many chiral/ asymmetric centers are in the following compounds? * - Warfarin has Three sp3 carbons - Only One sp3 carbons are asymmetric 14 Ass. Prof. Abeer Abdelazeem Mohamed  Stereoisomers  For chiral compounds, each pair of isomers is called an enantiomer (mirror image, non-superimposable).  Enantiomers are stereoisomers that are mirror image and non-superimposable.  They have the same physical properties (e.g., m.p., b.p., and solubility) except for optical activity.  Compounds that can interact with the plane-polarized light and rotate its plane either to the left or to the right are said to be optically active.  The simplest class of optically active molecules has one carbon bonded to four different substituents, and the carbon is said to be: asymmetric carbon, chiral carbon, or Enantiomer stereogenic carbon. mirror image, non-superimposable  Measurements of optical activity are carried out with a polarimeter. 15 Ass. Prof. Abeer Abdelazeem Mohamed  Optical Isomers Compounds that can interact with the plane-polarized light rotating its plane either to the left (anti-clockwise) or to the right (clockwise) are said to be optically active. Polarimeter 16 Ass. Prof. Abeer Abdelazeem Mohamed  Optical Isomers Specific rotation calculation The specific rotation is the number of degrees of rotation caused by a solution of 1.0 g/ ml of the compound in a sample tube 1.0 dm long at a specified temperature and wavelength. Specific rotation ‘α’: the observed rotation in degrees, ‘l’ : the length of the polarimeter cell in decimeters ‘c’ : the concentration of the sample in g per 100 cm3 ‘t’ : the temperature in ºC at which the measurement takes place ‘D’ : that light from the D line of a sodium lamp with a wavelength of 589.6 nm 17 Ass. Prof. Abeer Abdelazeem Mohamed  Optical Isomers  Enantiomers that rotate the plane to the right, i.e., clockwise, are called dextrorotatory and are sometimes given the symbol ‘d’ or the symbol (+).  Those that rotate to the left, anti-clockwise, are called levorotatory with the symbol ‘l’ or given the symbol (-).  A mixture of equal amounts of two enantiomers such as (R)-(-)-lactic acid and (S)-(+)-lactic acid is called a racemic mixture or a racemate. Racemic mixtures rotate the plane of polarized light in opposite directions and by the same amount, so they cancel each other and are said to be optically inactive. The symbol (±) is used to specify a racemic mixture. 18 Ass. Prof. Abeer Abdelazeem Mohamed (±) Butan-2-ol  Optical Isomers Optical Purity and Enantiomeric Excess  An enantiomerically pure sample means only one enantiomer is present.  If the sample has an observed specific rotation of 0°, the compound is a racemic mixture.  The %OPTICAL PURITY = specific rotation of the sample specific rotation of the pure enantiomer  Optical purity is often called ENANTIOMERIC EXCESS (ee).  “ee’’ tells us how much an excess of one enantiomer is in the mixture.  “ee” represents the difference between the % of one pure enantiomer and the % of the racemic mixture. 19 Ass. Prof. Abeer Abdelazeem Mohamed  Drawing enantiomers Perspective formulas Fischer Projection (S)-(+)-lactic acid (R)-(–)-lactic acid R- Glyceraldehyde S- Glyceraldehyde 20 Ass. Prof. Abeer Abdelazeem Mohamed  The R,S System of Nomenclature  It is a system of nomenclature that indicates the absolute configuration which is the arrangement of the atoms or groups about the asymmetric carbon.  Cahn, Ingold, and Prelog devised the R, S system (CIP Priority Rule).  Rank the groups (or atoms) bonded to the asymmetric carbon in order of priority. The atomic numbers of the atoms directly attached to the asymmetric center determine the priorities. The higher the atomic number, the higher the priority. CIP Increasing Priority Rule Orient the molecule so that the group (or atom) with the lowest priority (4) is directed away from you. Then draw an imaginary arrow from the group (or atom) with the highest priority (1) to the group (or atom) with the next highest priority. 21 Ass. Prof. Abeer Abdelazeem Mohamed  The R,S System of Nomenclature  If the arrow points clockwise, the asymmetric carbon has the R R-isomer 1 configuration (R is for rectus, which is 4 Latin for “right”). 3  If the arrow points counterclockwise, the asymmetric carbon has the S S-isomer 2 R configuration (S is for sinister, which is Latin for “left”). If there is a double bond, consider it as 2 single bonds If there is a triple bond, consider it as 3 single bonds 22 Ass. Prof. Abeer Abdelazeem Mohamed  The R,S System of Nomenclature 3 3 (H, H, H) 2 4 4 2 (O,O,O) 4 4 1 3 (H, H, C) 1 3 (H,H,H) 2 2 1 1 (S)-2-chloropentane (R)-2-chloropentane (S)-lactic acid (R)-lactic acid (H,H,O) (O,O,H) 23 Ass. Prof. Abeer Abdelazeem Mohamed  The R,S System of Nomenclature  If the group with the lowest priority (group 4) is not bonded by a hatched wedge ( i.e., not away from you):  Interchange group 4 with the group bonded by a hatched wedge.  Then draw an arrow from the group (or atom) with the highest priority (1) to the group (or atom) with the second highest priority (2). R S Actual configuration Because you have switched two groups, you are now determining the configuration of the enantiomer of the original molecule. So, if the arrow points clockwise, the enantiomer (with the switched groups) has the R configuration, which means the original molecule has the S configuration. In contrast, if the arrow points counterclockwise, the enantiomer (with the switched groups) has the S configuration, which means the original molecule has the R configuration. 24 Ass. Prof. Abeer Abdelazeem Mohamed  The R,S System of Nomenclature in Fischer Projection Rank the groups (or atoms) that are bonded to the asymmetric 1 carbon in order of priority. 3 2 Draw an arrow from the group (or atom) with the highest priority (1) to the group (or atom) with the next highest priority (2). If the arrow R points clockwise, the enantiomer has the R configuration; if it points 4 counterclockwise, the enantiomer has the S configuration, provided that the group with the lowest priority (4) is on a vertical bond 2  If the group (or atom) with the lowest priority is on a horizontal bond: 1 4 if the arrow points clockwise, it has the S configuration. 3 if the arrow points counterclockwise, it has the R configuration. S 25 Ass. Prof. Abeer Abdelazeem Mohamed  The R,S System of Nomenclature (H, H, O) 2 2 3 1 4 1 (O, O, O) 4 3 (H, H, C) S R 26 Ass. Prof. Abeer Abdelazeem Mohamed  The R,S System of Nomenclature Which of the following structures is the active form of Ibuprofen, given that the active form is the S form? 4 3 (H, H, H) 3 4 2 2 1 1 (O, O, O) (C, C, C) (A) R (B) S Thus, (B) is the active form of Ibuprofen 27 Ass. Prof. Abeer Abdelazeem Mohamed  Relative configuration (D, L)  It is the arrangement of the substituents about the chiral center (for amino acids, and carbohydrates).  Compounds with the same relative configuration as (+)-glyceraldehyde, were assigned the ‘D’ prefix, and those with the relative configuration of (-)-glyceraldehyde were given the ‘L’ prefix.  There is no correlation between configuration and the sign of rotation. If the OH group on the last chiral carbon from the bottom of the sugar is directed to the left. If the OH group on the last chiral carbon from the bottom of the sugar is directed to the right. Chiral center D- (+)-Glyceraldehyde L-(-)-Glyceraldehyde Last Chiral center Chiral center 28 Ass. Prof. Abeer Abdelazeem Mohamed  Assignment Do the following structures represent identical molecules or a pair of enantiomers? (a) (b) 29 Ass. Prof. Abeer Abdelazeem Mohamed  Assignment How many chiral centers are in the following structures? Testosterone 1,2-Dimethylcyclohexane Prostaglandin E1 Thalidomide 30 Ass. Prof. Abeer Abdelazeem Mohamed  Assignment Butaclamol is a potent antipsychotic that has been used clinically in the treatment of schizophrenia. How many asymmetric centers are present in Butaclamol? 31 Ass. Prof. Abeer Abdelazeem Mohamed 32 Ass. Prof. Abeer Abdelazeem Mohamed 33 Ass. Prof. Abeer Abdelazeem Mohamed