Stereochemistry Org I Pharm D Clinical PDF

Stereochemistry (Chiral Molecules)  The Greek word stereos means “solid”, and stereochemistry refers to chemistry in three dimensions. Our major objective in this course is to develop a feeling for molecules as three-dimensional objects and become familiar wi...

Stereochemistry (Chiral Molecules)  The Greek word stereos means “solid”, and stereochemistry refers to chemistry in three dimensions. Our major objective in this course is to develop a feeling for molecules as three-dimensional objects and become familiar with stereochemical principles, terms and notations. A full understanding of organic and biological chemistry requires awareness of the spatial requirements for interactions between molecules. Here we provide the basis for that understanding. SUBDIVISION OF ISOMERS Isomers are different compounds that have the same molecular formula.  Types of structural (constitutional) isomers Constitutional isomers are isomers that differ because their atoms are connected in a different order. 1- Chain or Skeletal isomers: They differ in their carbon skeleton (i.e, chain). e.g: C5H12 (n- pentane, isopentane and neopentane). 2- Positional isomers: They differ in the position of the existing functional group e.g., C5H11OH. 3- Functional group isomers: They are different in the types of function group, e.g. Ketones, alcohols & ethers. [have totally different properties] 4- Metameric isomers: They differ in the number of alkyl group attached to either side of a functional group (limited to divalent atoms as O or S, as in case ethers and thioethers) 5- Tautomerism: Tautomer (Greek: Tauto=same, meros=parts) This isomerism is due to spontaneous interconversion of two isomeric forms with different functional groups. The prerequisites for this is the presence of the C=O, C=N or N=O in the usual cases and an alpha H atom. Such compound exists as a mixture of two function group isomers in equilibrium with each other as a result of reversible migration of a hydrogen atom (and /or a valence bond).  Types of Tautomerism: The equilibrium is obtained by 1,3-migration of hydrogen atom. a) Keto-Enol Tautomerism b) Imine-Enamine Tautomerism c) Oxime-Nitroso Tautomerism a) Keto-Enol Tautomerism b) Imine-Enamine Tautomerism c) Oxime-Nitroso Tautomerism Stability of Keto form vs Enol form: The keto form is, in general, more stable than its enol tautomer. The keto form is therefore favored at equilibrium because it is the lower energy form (>99%). Q. When can the Enol form exist in a higher percentage? A. If it is stabilized. !!!! 1] Aromaticity. 2] H-Bonding.  Can these compounds show tautomerism? If yes, then draw their tautomers. SUBDIVISION OF ISOMERS Stereoisomers differ only in arrangement of their atoms in space. Difference between configurational and conformational isomers  Configurational Stereoisomers a) Geometric stereoisomers b) Optical stereoisomers 1.Enantiomers are stereoisomers whose molecules are nonsuperimposable mirror images of each other. 2. Diastereomers are stereoisomers whose molecules are not mirror images of each other. Enantiomers & Chiral Molecules A chiral molecule is one that is not identical with its mirror image. Objects (and molecules) that are superimposable on their mirror images are achiral. Chirality=handedness!!  Three-Dimensional Representations: 1-Wedge-Dash Notation In this notation, two bonds are drawn in the plane of the page (sticks), one bond is drawn coming toward you, out of the page (wedged), and one bond is drawn going away from you, behind the page (dashed). In the structure above, the alcohol on the second carbon is behind the page. Since there must be four bonds to each carbon, and two sticks and one dash have been drawn in, the remaining hydrogen must be wedged.  Three-dimensional drawings of the 2-butanol enantiomers I and II. An unsuccessful attempt to Models of the 2-butanol enantiomers. superpose models of I and II.  Chiral compounds chiral carbons!!! Chiral Carbons : 1. tetrahedral Sp3 hybridized carbon 2. have 4 different attached substituents This tetrahedral atom with four different groups attached to it is a stereocenter (chiral center, stereogenic center) = asymmetric carbon. The tetrahedral carbon atom of 2-butanol that bears four different groups. [By convention, such atoms are often designated with an asterisk (*)].  2-Propanol is achiral. (Why?) Mirror H H HO C C OH H3C COOH HOOC CH 3 (+)-Lactic acid, []D = +3.82 (−)-Lactic acid, []D = -3.82 Lactic Acid is chiral. (Why?)  The Biological Importance of Chirality Chirality is a phenomenon that pervades the universe. Humans are chiral or at least parts of them ☺  Helical Seashells are chiral. All but one of the 20 amino acids that make up naturally occurring proteins are chiral.  The origin of biological properties relating to chirality: The fact that the enantiomers of a compound do not smell the same suggests that the receptor sites in the nose for these compounds are chiral, and only the correct enantiomer will fit its binding site (just as a hand requires a glove of the correct chirality for a proper fit).  Tests for Chirality: Planes of Symmetry 1] Presence of a single tetrahedral stereocenter. 2] Mirror image is not superimposable. 3] Absence of elements of symmetry; a plane of symmetry or center of symmetry (inversion center). A plane of symmetry (also called a mirror plane) is an imaginary plane that bisects a molecule in such a way that the two halves of the molecule are mirror images of each other. A center of symmetry (inversion center) is a point in the molecule - not necessarily on an atom - through which all other atoms can be reflected 180 degrees into another, identical, atom. (a)2-Chloropropane has a plane of symmetry and so is achiral (b)2-Chlorobutane doesn’t have a plane of symmetry and so is chiral  Symmetry plane NO ymmetry plane OH HO H H H CH3 C C COOH COOH HO−CH2COOH CH3CH(OH)COOH Hydroxyacetic acid Lactic acid (achiral) (chiral)  Assign the chiral centers in the following compounds & detect whether the compound is chiral or achiral.  Structures F and G are achiral. The former has a plane of symmetry passing through the chlorine atom and bisecting the opposite carbon- carbon bond. The similar structure of compound E does not have such a symmetry plane, and the carbon bonded to the chlorine is a chiral center (the two ring segments connecting this carbon are not identical). Structure G is essentially flat. All the carbons except that of the methyl group are sp2 hybridized, and therefore trigonal-planar in configuration. Compounds C, D & H have more than one chiral center, and are also chiral. Remember, all chiral structures may exist as a pair of enantiomers.  Properties of Enantiomers (Optical Activity) Enantiomers have identical physical properties such as boiling points, melting points, refractive indices, and solubilities in common solvents except optical rotations. Many of these properties are dependent on the magnitude of the intermolecular forces operating between the molecules, and for molecules that are mirror images of each other these forces will be Identical. Enantiomers rotate the plane of plane-polarized light in equal amounts but in opposite directions. Separate enantiomers are said to be optically active compounds. Enantiomers show different behavior only when they interact with other chiral substances. Enantiomers show different rates of reaction towards other chiral molecules Enantiomers show different solubilities in chiral solvents. Plane-Polarized Light A beam of light consists of two mutually perpendicular oscillating fields: an oscillating electric field and an oscillating magnetic field. Oscillations of the electric field (and the magnetic field) are occurring in all possible planes perpendicular to the direction of propagation.  Plane-polarized light: When ordinary light is passed through a polarizer, the polarizer interacts with the electric field so that the electric field of the light emerges from the polarizer (and the magnetic field perpendicular to it) is oscillating only in one plane. The Polarimeter  A substance that rotates plane-polarized light in the clockwise direction is said to be dextrorotatory, (d) , the rotation, α (measured in degree) is said to be positive (+) And one that rotates plane-polarized light in a counterclockwise direction is said to be levorotatory , (l) the rotation is said to be negative (–). (Latin: dexter, right; and laevus, left). The Origin of Optical Activity Almost all individual molecules, whether chiral or achiral, are theoretically capable of producing a slight rotation of the plane of plane-polarized light. If the beam of plane-polarized light passes through a solution of an achiral compound, the beam should encounter at least one molecule that is in exactly the mirror image orientation of the first before it emerges from the solution  cancels the first rotation. Because billions of molecules are present, it is statistically certain that for each encounter with a particular orientation there will be an encounter with a molecule that is in a mirror- image orientation  optically inactive.  If the beam of plane-polarized light passes through a solution of a chiral compound, no molecule is present that can ever be exactly oriented as a mirror image of any given orientation of another molecule  optically active. Racemic Forms & Enantiomeric Excess (e.e.) Racemic Forms: A 50:50 mixture of the two chiral enantiomers. A sample of a racemic mixture of an optically active substance is optically inactive. Ex. A racemic mixture of 1:1 (S)-(+)-2-butanol & (R)-(-)-2-butanol shows a specific rotation of zero ([α]D = 0)  Optical Activity & the Specific Rotation [] The specific rotation depends on the temperature (T) and wavelength (Na D-line: 589.6 nm) of light that is employed. The magnitude of rotation is dependent of the solvent when solutions are measured.  Enantiomeric Excess (e.e.) A sample of an optically active substance that consists of a single enantiomer is said to be enantiomerically pure or to have an enantiomeric excess of 100%. Ex. An enantiomerically pure sample of (S)-(+)-2-butanol shows a specific rotation of 13.52 ([α]D = +13.52) On the other hand, a sample of (S)-(+)-2-butanol that contains less than an equimolar amount of (R)-(-)-2-butanol will show a specific rotation that is less than 13.52 but greater than zero. Such a sample is said to have an enantiomeric excess less than 100%.  Ex. A mixture of the 2-butanol enantiomers showed a specific rotation of +6.76. calculate the enantiomeric excess of the (S)-(+)-2-butanol ([α]D = +13.52) ??? % ee = (+6.76 / +13.52) X 100 = 50 % This means that 50% of the mixture consists of the (+) enantiomer (the excess) and the other 50% consists of the racemic form. The 50% that is racemic the optical rotations cancel one another out, thus, only the 50% of the mixture that consists of the (+) enantiomer contributes to the observed optical rotation. The observed rotation is, therefore, 50% (or one-half) of what it would have been if the mixture had consisted only of the (+) enantiomer.  A sample of pure (S)-2-butanol was placed in a 10.0 cm polarimeter tube. Using the D line of a sodium lamp, the observed rotation at 20oC was α = +104o. The density of this compound is 0.805 g ml-1. What is the specific rotation of (S)-2-butanol? Calculate the observed rotation of a solution of 0.5245g of (S)-1- amino-1-phenylethane diluted to a volume of 10.0 mL with methanol at 20oC, using the D line of a sodium lamp and a 1.00 dm tube. Specific rotation of this material: [α]D23 = -30.0o. A mixture contains 3g of (+)-2-bromobutane and 2g of (–)-2- bromobutane. What is the rotation of the mixture, given that (+)- 2-bromobutane has a specific rotation of +23.1°. A sample of 2-butanol has an optical rotation αobs = -5o, if the specific rotation for pure sample [α]D = -13.52; then what is the enantiomeric excess (ee)? Calculate the percentage of the (+) & (-) isomers. 1- A sample of pure (S)-2-butanol was placed in a 10.0 cm polarimeter tube. Using the D line of a sodium lamp, the observed rotation at 20oC was α = +104o. The density of this compound is 0.805 g ml-1. What is the specific rotation of (S)-2-butanol? The answer: Specific rotation = +104/1dm*0.805= +129.19o 2- Calculate the observed rotation of a solution of 0.5245g of (S)-1-amino-1- phenylethane diluted to a volume of 10.0 mL with methanol at 20oC, using the D line of a sodium lamp and a 1.00 dm tube. Specific rotation of this material: [α]D23 = -30.0o. The answer: -30= Observed rotation/0.0524= -1.572o 3- A mixture contains 3g of (+)-2-bromobutane and 2g of (–)-2-bromobutane. What is the rotation of the mixture, given that (+)-2-bromobutane has a specific rotation of +23.1°. The answer: No. of moles of (+)-2-bromobutane = 3/137= 0.0218 No. of moles of (-)-2-bromobutane = 2/137= 0.0145 Total no of moles= 0.0218+ 0.01475= 0.0365 Optical purity= 0.0218-0.0145/0.0367 *100= 20% 20%= rotation of mix/+23.1 Rotation of the mixture = +4.62o 4- A sample of 2-butanol has an optical rotation αobs = -5o, if the specific rotation for pure sample [α]D = -13.52; then what is the enantiomeric excess (ee)? Calculate the percentage of the (+) & (-) isomers. The answer: %Optical purity= 5/13.52 *100= 37% EE = 37% Racemic mixture= 100-37= 63% (+31.5, -31.5) 31.5% (+) 31.5 + 37= 68.5% (-)  Nomenclature of Enantiomers: (The R-S system) Three chemists, R. S. Cahn (England), C. K. Ingold (England), and V. Prelog (Switzerland), devised a system of nomenclature. This system, called the R,S-system or the Cahn–Ingold– Prelog system (CIP system), is part of the IUPAC rules. According to this system, any compound having one chiral center should be designated (R)-isomer and the other enantiomer should be designated (S)-isomer. (R) and (S) are from the Latin words rectus and sinister, meaning right and left, respectively. These molecules are said to have opposite configurations at the designated chiral center (stereocenter).  The (R-S) System: (Cahn-Ingold-Prelog System) The absolute configuration Each of the four groups attached to the stereocenter is assigned a priority. 1] Priority is first assigned based on the atomic number (Z) of the atom that is directly attached to the stereocenter. 2] In the case of isotopes, the isotope of greatest atomic mass has highest priority. 3] When a priority cannot be assigned based on the atomic number of the atoms that are directly attached to the stereocenter, then the next set of atoms in the unassigned groups are examined. 4] Make sure that no 4 atom (least priority is at the back)  View the molecule with the group of lowest priority pointing away from us. 1) If the direction from highest priority to the next highest to the next is clockwise, the enantiomer is designated R. 2) If the direction is counterclockwise, the enantiomer is designated S. 4] Groups containing double or triple bonds are assigned priority as if both atoms were duplicated or triplicated. (Y) (C) C Y as if it were C Y C Y as if it were C Y (Y) (C) (Y) (C) 5] If the lowest priority group is not pointing away from us (not dashed bond), then how can we assign the absolute configuration? Double switching gives S-enantiomer the same enantiomer  No correlation exists between the configuration (R, S designation) of enantiomers and the direction of optical rotation. Molecules with More than One Stereocenter Diastereomers: are stereoisomers that are not mirror images to each other. Threonine (2-amino-3-hydroxybutanoic acid) Enantiomers must have opposite (mirror-image) configurations at all stereogenic centers. No of stereoisomers= 2n  Diastereomers must have opposite configurations at some (one or more) stereogenic centers, but the same configurations at other stereogenic centers. No of diastereomers= 2n-1 Diastereomers Diastereomers Meso Compounds A Meso compound: Has chiral centers, but it is not itself Chiral, this is because it has a plane of symmetry within the molecule.  It is easy to recognize when a compound with two asymmetric carbons has a stereoisomer that is a meso compound—the four atoms or groups bonded to one asymmetric carbon are identical to the four atoms or groups bonded to the other asymmetric carbon. A compound with the same four atoms or groups bonded to two different asymmetric carbons will have three stereoisomers: One will be a meso compound, and the other two will be enantiomers. I get 2 enantiomers and one meso stereoisomer which its mirror image is the same compound.  2- Fischer Projections Fischer Projections are used often in drawing sugars and hydrocarbons, because the carbon backbone is drawn as a straight vertical line, making them very easy to draw. When properly laid-out, Fischer Projections are useful for determining enantiomeric or diasteromeric relationships between two molecules, because the mirror image relationship is very clear.  In a Fischer Projection, each place where the horizontal and vertical lines cross represents a carbon. The vertical lines are oriented away from you (like dashes in the Wedge-Dash Notation) and the horizontal lines are oriented toward you (like wedges in the Wedge- Dash Notation). Memory Aid ? (this one works for me 100% of the time!) A student once told me that she remembered the relative arrangement of the bonds by the fact that the horizontal bonds were coming out to hug her ! Allowed motions for Fischer projections: 1. 180° rotation (not 90° or 270°): 2. 90° rotation: Rotation by 90° inverts its meaning.  COOH COOH H OH Same as H C OH (R)-Lactic acid CH3 CH3 90o rotation OH OH HOOC CH3 Same as HOOC C CH3 (S)-Lactic acid H H 3. One group hold steady and the other three can rotate: Hold steady COOH COOH H OH Same as HO CH3 CH3 H Assigning R & S configurations to Fischer projections 1) Assign priorities to the four substituents. 2) Perform one of the two allowed motions to place the group of lowest (fourth) priority at the top of the Fischer projection. 3) Determine the direction of rotation in going from priority 1 to 2 to 3, and assign R or S configuration. Fischer Projections of compounds with more than 1 stereocenter: R-S configuration: Enantiomers, Diastereomers or Meso compounds  Chiral Drugs Many Drugs were marketed as a racemate for years even though only one enantiomer is the active agent. Recently the FDA & pharmaceutical industry has more interest in the production & sale of “chiral drugs”. Example. Only the (S) enantiomer is active while the (R) enantiomer has no anti-inflammatory action. The (R) enantiomer is slowly converted to the (S) enantiomer in the body, so the racemate works slower than the enantiopure medicine (S-isomer).  D-Penicillmine The (S) isomer is used for treatment of arthritis. The (R) enantiomer is highly toxic. As a result, enantioselective synthesis and the resolution of racemic drugs (separation into pure enantiomers) became active areas of research today to obtain enantiomerically pure drugs to improve the drug potency & safety.  Newman Projections Newman Projections are used mainly for determining conformational relationships. Conformers are molecules that can be converted into one another by a rotation around a single bond. In this notation, you are viewing a molecule by looking down a particular carbon-carbon bond. The front carbon of this bond is represented by a dot, and the back carbon is represented by a large circle. The three remaining bonds are drawn as sticks coming off the dot (or circle), separated by one another by 120 degrees.