Pharmaceutical Organic Chemistry 1 (PMC 102) Lectures 3-6 PDF

Pharmaceutical Organic chemistry 1 (PMC 102) Lectures 3-6  Stereochemistry  Stereochemistry is concerned with isomerism in a three dimensional spaces.  Isomers: are different compounds having the same molecular formula.  Classification of isomer...

Pharmaceutical Organic chemistry 1 (PMC 102) Lectures 3-6  Stereochemistry  Stereochemistry is concerned with isomerism in a three dimensional spaces.  Isomers: are different compounds having the same molecular formula.  Classification of isomers: A. Constitutional Isomers (Structural Isomerism) This type of isomerism occurs in between compounds having the same molecular formula but they have different structures. 1. Chain isomers (skeletal isomers) 2. Positional isomers. 3. Functional isomers B. Stereoisomerism 1. Optical isomerism. 2. Geometrical isomerism.  1. Chain isomers  These are isomers that differ in the mood of arrangement of carbon skeleton. CH3 H2 H2 H3C CH H3C C C CH3 CH3 n-Butane (straight chain) Isobutane (branched) CH3 CH3 H2 H2 H2 H2 H3C C CH3 H3C C C C CH3 H3C C C CH3 H CH3 n-Pentane Isopentane Neopentane  2. Positional isomers:  These are isomers having the same functional group but differ in its position.  Ex: C3H8O OH H2 H2 H3C C C OH H3C C CH3 H 1-Propanol 2-Propanol  2. Positional isomers:  Ex: C6H5NO3 OH OH OH NO2 NO2 NO2 o-Nitrophenol m-Nitrophenol p-Nitrophenol  Ex: C4H8O OH OH H2 H2 H3C C C COOH H3C C C COOH H H 2-Hydroxybutanoic acid 3-Hydroxybutanoic acid  3. Functional group isomers:  these are isomers having the same mol. formula but different functional groups. The two isomers belong to two different classes of compounds.  Ex: C2H6O CH3CH2OH H3C O CH3 Ethyl alcohol Dimethyl ether O  Ex: C3H6O CH3CH2CHO H3C C CH3 Propionaldehyde Acetone (Propanal)  B. Stereoisomerism  In this type of isomerism the two compounds have the same molecular formula and the same functional group but with different configurations (arrangement in space). 1. Optical isomers:  These are isomers have the same physical and chemical characters but have different influence on the plane of plane-polarized light. One isomer would rotate the plane of plane-polarized light to the right while the other rotates it to the left.  2. Geometrical isomers:  These are isomers having different configuration and is noticed whenever there is a restricted rotation.  Ex: in olefinic compounds and in cycloalkanes: R R R H R R R C C C C H H H R R Cis Trans Cis Trans Conformational (Rotational) Isomerism  This term denotes any of the indefinite number of structures that may result by simple rotation around single bonds.  These structures are inter-convertible and each one contains a definite quantity of energy.  Each structure called conformer, at equilibrium the better contribution is by conformer containing the least amount of energy.  The best ways for presentation, of conformers resulting from the free rotation of groups around carbon-carbon single bonds are:  1. Sawhorse projection:  It is the side view for two adjacent atoms. The bond joining the two atoms is considered to be in the plane of the paper and the remaining bonds project above or below the plane (ex: Ethane CH3-CH3). Eclipsed Staggared  1. Sawhorse projection: N.B.  The single bond between the two central C atoms must be (√) (x) slightly oblique.  The axis of the carbon atom axis must be on the plane of the (√) (x) paper.  Single bond which represent as " " must be on the right of the axis. (x) (√) (√)  2. Newman projection:  It is viewed along the bond joining the two adjacent atoms, these two atoms become superposed. Eclipsed Front C-atom Rear C-atom Staggered (back) Conformational (Rotational) Isomerism H H H H Rotation 60o Rotation 60o H H H H H H H H H H H H H H HH H HH H H H H H H H H H H H H H Eclipsed Staggered Eclipsed In eclipsed conformer there is repulsion between each C-H bond and the opposite C-H bond. So it has maximum energy and so unstable. By rotation 60o around C-C single bond the repulsion decrease till it became very small (staggered conformers) Conformational (Rotational) Isomerism  Energy Diagram of ethane Conformations: HH I I I I Energy Content of Eclipsed Conformations H H I H H H H H II II II Staggered H H II 120o 180o 240o 300o H 60o Angle of Rotation  The shape of this curve (ethane conformers) is symmetric because all substituents are the same type (H atoms). Conformational (Rotational) Isomerism  The shape of energy diagram will become different in case of more substituted paraffins such as 1,2-dichloroethane n-butane Cl CH3 C C H H H H Cl CH3 C C H H H H  For 1,2-dichloroethane the following conformations by rotation of one of the carbons around the C-C single bond starting from the fully eclipsed conformer. Sawhorse projection formula of Cl-CH2-CH2-Cl H H H Cl H Rotation 60o Cl Rotation 60o Cl H H H H H H H H Cl Cl Cl Fully Eclipsed I Skew or Gauch II Cl-H Eclipsed III H Cl H Cl 60o 60o H H Cl Rotation 60o H Rotation 60o H H H H H H H Cl Cl Cl Anti-conformer IV Skew or Gauch II Cl-H Eclipsed III (most stable) Newman projection formula of Cl-CH2-CH2-Cl H H H Cl H H H o H H Rotation 60o H H Rotation 60 Cl H Cl Cl Cl H Cl Fully Eclipsed I Skew or Gauch II Cl-H Eclipsed III 60o o 60 H Cl H Cl H H o H H o H H Rotation 60 Rotation 60 H Cl H H Cl H Cl Cl Skew or Gauch II Cl-H Eclipsed III Anti-conformer IV (most stable)  Anti-conformer (IV) is the most stable have the minimum amount of energy. In this conformer the chlorine atoms are on the same plane but in opposite direction.  Fully eclipsed conformer (I) is the most unstable, it have maximum energy as a result to big repulsion between the two chlorine atoms I I Energy Content of Conformations III III II II IV 60o 120o 180o 240o 300o Angle of Rotation  Optical Isomerism  To study the optical isomers we must study light:  Nature of white light (normal light)  The white light is a mixture of various electromagnetic waves each of a different wave length (λ) and vibrates in perpendicular plane on direction of transmission.  Plane- polarized light This can be defined as being a monochromatic light vibrating only in one selected plane.  To obtain a plane polarized light a ray of monochromatic light is passed through a prism which is formed of a bisected calcite crystal (CaCO3). This prism passes only the rays that are parallel to its axis of symmetry.  When this plane-polarized light traverses an optically active substance it will suffer plane rotation thus making an angle with the original plane (α). This angle can either be to the right (dextro rotation) or to the left (levo rotatio  The angle of rotation [α] can be calculated by “Polarimeter”  Polarimeter consists of four essential parts: 1. A source of light. 2. Prism: (polarizer) to obtain plane-polarized light. 3. Sampling tube: to hold the solution of the sample under investigation. 4. Another prism: (analyzer) can be rotated relative to the polarizer. When the analyzer is perpendicular to the polarizer no light passes. When both prisms are parallel it passes the plane- polarized ray without any change in its intensity.  When the plane-polarized light passes through an optically active compound it will suffer plane rotation. The analyzer is then rotated by a certain angle [α]. The value of [α] can be (+) or (-) and it is affected by:  Temperature (t).  Wave length () of plane-polarized light utilized.  Concentration of the substance to be analyzed (c).  The length of the sampling tube (l).  Specific Rotation t  [] =  cl  α: the recorded angle of rotation  c: g/ml  l: decimeter  Optical Isomerism  Requirements of compounds to be optically active; substance can exhibit optical activity when it is non super imposable with its mirror image.  Such type of compounds should either have: 1. One or more asymmetric atoms (chiral center or stereocenter). 2. An asymmetric molecule (chiral molecule) i.e. a molecule lacking a plane of symmetry.  Plane of symmetry: An imaginary plane that bisects the molecule into two identical halves mirror image to each other. COOH H OH Plane of symmetry H OH COOH  Optically Active Compounds Containing One Asymmetric Atom  An asymmetric carbon atom can a be defined as that atom whose a four valencies are joined to four b b different atoms or groups c d d c  Ex: 2-Hydroxybutane CH3 CH3 C2H5 C2H5 OH HO H H d or (+) Enantiomers l or (-) Enantiomers: They are two stereoisomers mirror image to each others and non-superimposable, one rotates the light to right and the other to the left.  Basic Terminology in Stereochemistry  Enantiomers: These are pairs of compounds that have similar physical and chemical characters but differ in action on the plane of plane-polarized light. Enantiomeric compounds are mirror-images to each other and rotate the plane of plane-polarized light to the right i.e. dextro (+) or to the left i.e. levo (-).  Basic Terminology in Stereochemistry  Diasteriomers: These are compounds having more than one chiral center and they are having the same sequence of atoms but are not mirror image to each others. Ex: 2,3-Dihydroxybutanoic acid COOH COOH COOH COOH H OH HO H H OH HO H H OH HO H HO H H OH CH3 CH3 CH3 CH3 Enantiomers Diasteriomers Enantiomers  Basic Terminology in Stereochemistry  Meso compounds: In this type of compounds, in spite of the presence of two or more asymmetric carbons (chiral carbons) the molecules can show no optical activity. Meso compounds have a plane of symmetry and are said to be optically inactive by internal compensation (can’t be resolvable) Ex: Meso tartaric acid COOH H OH Plane of symmetry H OH COOH  Basic Terminology in Stereochemistry  Racemic modification: This is a mixture of equal amount of both enantiomers and this modification is optically inactive by external compensation. It differs from meso compounds in being resolvable into its forming enantiomers. Racemic mixture can also be named dl pairs or (±) pairs.  Chirality: This expresses the requirements necessary for a molecule to exist in two enantiomeric forms. Chiral molecule ≡ optically active Achiral molecule ≡ optically inactive  Atropisomerism: This is the optically activity caused by restricted rotation a phenomena that cause the molecule to contain no plane of symmetry. Ex: Biphenyl compounds, allenes, Spiro compounds....  Graphical Stereochemistry Representation A. Newman projection formula. B. Sawhorse projection formula. C. Fischer projection formula (for chiral molecules).  Rules of Fischer projection formula  This representation facilitates the drawing of the three dimentional molecule on a two dimentional surface.  When dealing with molecule containing more than one chiral center, it should be first in eclipsed conformer.  The chiral carbons are given the plane of the drawing surface.  All the carbons are written vertically with C1 at the top.  The 2 groups projecting above the plane are horizontal and those behind as two vertical lines.  OH H  Ex: 2,3-dihydroxypropanal H2 * HO C C C O H 3 2 1 Behind the plane CHO CHO but we can Above Above HO C H the plane H OH the plane represent it as CH2OH CH2OH Chiral center Behind on the plane the plane  It is not allowed to rotate the formula within the plane by 90o or 270o (this cause inversion of configuration) although it is allowed to rotate by 180o.  It is not allowed to exchange one pair of the four groups join to the chiral carbon (cause inversion of configuration)  It is allowed to switch the four groups around the chiral center in pairs (double switch).  It is allowed to rotate three groups around the chiral center in one direction while fixing the fourth one.  Ex: 2-Butanol OH * H3C CH CH2CH3 CH3 OH double switch H OH C2H5 CH3 C2H5 H rotating 3 groups in one direction around the chiral center and fix the fourth group OH These are allowed and cause H3C H retension of configuration C2H5 How can we draw the Fischer projection formula from either Sawhorse or Newman projection formula? Br H CH3 H CH3 H CH3 H OH Br H OH H OH Br CH3 at the top CH3 CH3 we look from this side 1 CH3 4 CH3 HO H Br H 2 180o 3 H Br H OH 3 2 CH3 CH3 4 3-Bromo-2-hydroxybutane 1 When we convert either Sawhorse or Newman projection formula to Fischer projection formula, we put it into the eclipsed conformer.  Compounds with Two Asymmetric Carbon Atoms 1. When the two asymmetric atoms are unequal  This means that the two sets of the four different groups joined to the two asymmetric carbon atoms are not equal.  Number of optical isomers = 2n (n = number of chiral centers)  Number of pairs of enantiomers = 2n-1 = 1/2 the number of optical isomers.  OH OH OH  Ex: 2,3,4-trihydroxybutanal * * H2C C C CHO H H  Number of optical isomers = 22 = 4  Number of pairs of enantiomers = 22-1 = 2 Drawing this molecule by Fischer projection formula CHO CHO CHO CHO H OH HO H HO H H OH H OH HO H H OH HO H CH2OH CH2OH CH2OH CH2OH ± Erythrose ± Threose  ± Erythrose and ± threose are two enantiomeric pairs and any erythrose is diasteriomeric with any threose.  Enantiomers should have two opposite signs while any diasteriomeric relation may or may not involve opposite signs.  Compounds with Two Asymmetric Carbon Atoms 2. When the two asymmetric atoms are equal  (They have the same four different groups)  Ex: Tartaric acid OH OH * * HOOC C C COOH H H COOH COOH COOH COOH I II III IV H OH HO H HO H H OH H OH HO H H OH HO H COOH COOH COOH COOH Optically Inactive ± Tartaric acid have a plane of symmetry Optically Active Meso forms of tartaric acid isomers  Compounds I and II are the same molecules because by rotation one of them get the other one: COOH COOH H OH HO H 180o H OH HO H COOH COOH  From the above, it is possible to identify four types of tartaric acid:  (+) tartaric acid (dextrorotatory)  (-) tartaric acid (levorotatory)  Meso tartaric acid.  Racemic mixture (mixture of +, -)  Configuration is the arrangement of atoms or groups around the asymmetric centre or the rigid part of the molecules (ring).  N.B. : The sign of rotation + or - has no relation with configuration.  Nomenclature of Configuration I. The D and L system In carbohydrate and Amino acid chemistry. H O H O C C H OH HO H CH2OH CH2OH D(+) Glyceraldehyde L(-) D & L isomers of glyceraldehyde serve as configurational standards to all monosaccharides. If the lower most chiral atom of the sugar having the OH group to the right, it is D isomer and vice versa.  H O C COOH HO H H2N H CH2OH R L(-) L-−amino acid Glyceraldehyde II. The R and S system : (the sequence rule) The asymmetric part is to be represented by a three dimentional formula (group on the plane, above and behind). The four atoms around the asymmetric carbon atom are arranged in a decreasing order of atomic number. When the asymmetric center is joined to two similar atoms, the next atoms are to be considered.  II. The R and S system : (the sequence rule) 4. In Assigning the sequence of arrangement, it is to be considered that : O N N C=O C C N C=N C N C O N N 5. The molecule is viewed from the opposite side of the atom having the lowest atomic weight, and a curve is down from the higher to the lower for the remaining three atoms. 6. If the direction of the curve is to the right, (clockwise) the asymmetric center is (R) or rectus and if is directed to the left (anticlockwise) it is called (S) or sinester.  Ex. : Glyceraldehyde OH HO H2C CH CHO * (2) CHO CHO (4) (1) H OH H C OH CH2OH CH2OH (3) R-Configuration (clockwise) (2) CHO CHO (1) (4) HO H HO C H CH2OH CH2OH (3) S-Configuration (Anticlockwise)  A more convenient and rapid technique : The groups around the asymmetric center are switched in pairs so as to get the group carrying number four (4) in the lowest position of the Fisher's projection formula. A curve is drawn joining in the sequence 1,2,3. (1) CHO OH Double (2) H OH HOH2C CHO (3) Switch CH2OH H (4) (R) (1) CHO OH OH H OHC CH2OH (2) (3) CH2OH H (4) (S)  (1)  Lactic acid COOH OH H OH H3C COOH (3) (2) OH CH3 H (4) H3C CH COOH (R) * (1) COOH CHO OH H HOOC CH3 (2) (3) CH3 H (4) (S) 2 1  Tartaric acid (2) 1 3 2 COOH 4 OH OH (4) (1) H OH 3 4 (R) HOOC CH CH COOH * * (4) HO H 3 1 COOH (3) 1 4 3 2 (R,R) Tartaric acid (2R,3R)-2,3-Dihydroxy 2 4 (R) butanedioic a cid  Write the structure of the following compounds : COOH  (2S, 3R)-2-Amino-3- HO H hydroxybutanoic acid H NH2 CH3  (2R, 3S)-2,3-dihydroxybutane CH3 HO H HO H CH3  Resolution of Racemic Modification  Racemic modifications are optically inactive by external compensation as it contain both the + and the – enantiomers together. Obtaining pure enantiomers from this mixture is known as resolution.  Resolution is an important process in nature as the desired action is only obtained from one and not the other enantiomer.  Geometrical Isomerism  This type of isomerism is noticed in molecule suffering from restricted rotation such as olefins (around C=C) and cycloalkanes (ring). H COOH HOOC H R R R H H H H R H COOH H COOH Cis Trans Cis Trans Maleic acid Fumaric acid  When the four groups are different; if the alkene is trisubstituted or tetrasubstituted, the terms cis and trans are not applied. we use the Z-E system based on the priority of groups (atomic number), we examine the two groups attached to one carbon atom of the double bond and decide which has higher priority. Then we repeat this operation at the other carbon atom. Cl F F Cl Cl > F Higher piriority Br > H Br H Br H Higher piriority (Z)-2-Bromo-1-chloro-1- (E)-2-Bromo-1-chloro-1- fluoroethene fluoroethene  We take the group of higher priority on one carbon atom and compare it with the H3C CH3 H3C H C C C C group of higher priority on H H H CH3 the other carbon atom. If the (Z)-2-Butene (or cis) (E)-2-Butene (or trans-2-butene) two groups of higher priority are on the same side of the double bond, the alkene is designated (Z) (from the Cl Cl Cl Br German word Zusammen, C C C C meaning together). If the two H Br H Cl groups of higher priority are (E)-1-Bromo-1,2-dichloroethene (Z)-1-Bromo-1,2-dichloroethene 2 1 H3C CH2 H2C CH2 - CH3 on opposite sides of the 4 C 3 C double bond, the alkene is H3C CH2 CH2 H2C 5 CH3 8 7 6 designated (E) (from the (E)-3-Methyl-4-n-propyl-3-octene German word entgegen, meaning opposite).  What is the relation between :  1,1-Dichloroethene and 1,2-Dichloroethene Cl Cl CH = CH - Cl C CH2 They are position isomers Cl Has geometrical isomers Has no geometrical isomers Has no configuration Cl Cl H Cl C C C C H H Cl H Cis Trans  Cl I C C Br H (E)-1-Bromo-1-chloro-2-iodoethene Br > Cl I > H CH3 CH3 HC 3 4 (E)-3-Methyl-4-isopropyl-3-nonene C C CH3 1 2 CH3CH2 CH2CH2CH2CH2CH3 5 6 7 8 9 1 CH3 H 2 3 C C H We put the configuration of both double bond 4 5 H C C (E, E)-2,4-Hexadiene H CH3 6 First Second H3C H double bond double bond 5 4 1 C C COOH (E, Z)-3,5-Dichloro-2-methyl-2,4-hexadienoic acid 3 2 Cl C C Cl CH3