Stereochemistry & stereoisomers

Stereochemistry The Arrangement of Atoms in Space or three dimensional structure of atoms. Stereoisomerism: is one aspect of stereochemistry. Isomers are compounds that have the same molecular formula but with different structures. There are two main classes of isomers: 1- Structural isomers (or constitutional isomers) 2- Stereo-isomers

I-Constitutional isomers: These are compounds whose atoms are connected differently . Different connections among atoms which may be due to difference in: A- Skeleton of carbon or B- Functional groups or C- Position of functional groups 4

II-Stereoisomers: These are compounds whose atoms are connected in the same order but with different geometry or arrangements. Types of Stereoisomers are: A- Optical isomers (e.g. enantiomers & configurational diastereomers) B- Geometric isomers or Cis &trans isomers or cis &trans stereomers (both in alkenes and cycloalkanes) 6

Enantiomers : These are non-superimposable mirror image stereoisomers. Diastereomers: Steroisomers which are not enantiomers are called diastereomers. A- configurational diastereomers: These are non-superimposable non-mirror image stereomers. B- cis-trans diastereomers: These contain substituents on same side or opposite side of double bond or ring (cyclic structure).

Cis-trans diastereomers Isomers constitutional isomers stereoisomers Optical isomers or Enantiomers Diastereomers: Configurational & Cis-trans diastereomers 8

Optical Isomerisms Optical Isomerisms: It manifests itself by its effect on plane-polarized light. Polarizers are used to produce plane-polarized light (e.g. polaroid film, nicol prism). Optical Activity Any compound that has the ability to change the direction of plane polarized light or to rotate it, is said to be optically active compound. Optical isomers are optically active substances. The rotation itself is called optical activity. 10

The diffrence between ordinary or plane-polarized light: A beam of ordinary light is vibrating in all possible planes perpendicularly, but Plane-polarized light is vibrating in only one of these possible planes. 11

Measurement of optical activity Polarimeters are used to measure the optical activities

Measurement of optical activity Plane polarized light passing through an optically active solution is rotated by a certain number of degrees alpha (α) called the “observed rotation”. If α found to be to the right (clockwise rotation), the optically active compound is designated as dextro-rotatory with the symbol (+). If α found to be to the left (counter clockwise rotation), is termed levo-rototatory with the symbol (-). 13

The observed rotation (α) depends upon: The concentration of the solution (C) The length of the polarimeter tube (L) The temperature (T) The wavelength of the light (λ)

Specific Rotation [α]D: The value of optical rotation of a compound under standard conditions is called the specific rotation. Thus specific rotation[α]Dof a compound is defined as the observed rotation when light of 589 nm wavelength is used with a sample path length (L) of 1 decimeter ( 1 dm = 10 cm) and a sample concentration (C) of 1 g/mL . (light of 589 nm, the so called sodium D line, is the yellow light emitted from common sodium lamps; 1 nm= 10-9 m.) [α]D = observed rotation (degrees) Path length, L (dm) X Concentration , C (g/mL) = α L X C 15

Specific rotation [α] The specific rotation is a physical constant characteristic of a compound Specific rotation [α] is mainly used for 1-Identification of compounds 2-Determining degree of purity 3-Determining the concentration 16

[α]D = α /L x c α = + 1.21 L= 5 cm = 0.5 dm C= 1.5 g/ 10 ml = 0.15 g/ml [α]D = + 1.21/ 0.5 x 0.15 = + 16.1o

Optical activity and structure of compounds

Optical activity and structure of compounds Chiral carbon atoms 4 different substituents on carbon, then it is no longer superimposable on its mirror image and we say that carbon is chiral . Carbon with 1,2,3 different atoms or groups attached can be superimposed on its mirror image and is achiral.

A molecule is achiral if its two mirror image forms are superimosable A molecule is chiral if two mirror image forms are not superimposable upon one another. A molecule is achiral if its two mirror image forms are superimosable The chiral centre is usually indicated by an asterisk (*) A molecule with a single chiral carbon must be chiral But, a molecule with two or more chiral carbons may be chiral or it may not. 3

Bromochlorofluoromethane is chiral It cannot be superimposed point for point on its mirror image. Cl Br H F 4

Bromochlorofluoromethane is chiral Cl Cl Br Br H H F F To show nonimsuperposability, rotate this model 180° around a vertical axis. 4

Properties of enantiomers Physical properties are the same: melting point, boiling point, density, etc. except properties that depend on the shape of molecule eg. [1]biological-physiological and [2]optical properties i.e, for direction of the plane polarized light. 11

a carbon atom with four different groups attached to it also called: The chiral carbon atom a carbon atom with four different groups attached to it also called: chiral center; chiral carbon asymmetric center asymmetric carbon stereocenter stereogenic center w x y z C 12

Chirality and chiral carbons A molecule with a single stereogenic center is chiral. 2-Butanol is an example. H C CH3 CH2CH3 OH 13

Examples of molecules with 1 chiral carbon CH2CH3 CH2CH2CH2CH3 CH3CH2CH2 one chiral alkane 13

Examples of molecules with 1 chiral carbon OH Linalool, a naturally occurring chiral alcohol 13

Examples of molecules with 1 chiral carbon CHCH3 1,2-Epoxypropane: a chiral carbon can be part of a ring attached to the chiral carbon are: —H —CH3 —OCH2 —CH2O 13

Enantiomers rotate light in equal amounts in opposite directions. (+) Dextrorotatory (Latin dexter is "right") (-) Levrorotatory (Latin levus is "left") A mixture consisting of equal parts of any pair of enantiomers is called a racemic mixture (or racemic modification) and is designated by (+/-). A racemic mixture does not rotate plane-polarized light because (+)-rotation caused by one enantiomer is canceled by rotation in the opposite direction by the (-)-enantiomer. A solution of a racemic mixture of enantiomers is optically inactive. 29

In racemic mixtures of drugs, the better fitting enantiomer is called the eutomer (Eu) while the lower affinity enantiomer is called the distomer (Dist). In racemic mixtures of drugs, the distomer should be viewed as an impurity comprising 50% of the mixture. An impurity that is by no means inert. Several implications of racemic drug treatment should be considered: Side effects Antagonist Metabolized to unfavorable metabolite Metabolized into a toxic metabolite

PREFIXES USED TO DENOTE CHIRAL PROPERTIES PREFIX PROPERTY d-/l- Rightward (dextro), clockwise/Leftward (leuvlo), counterclockwise, optical rotation. Used interchangably with (+)/(-) D-/L- Rightward/leftward arrangement of substituents about chiral center (archaic, used for amino acids & carbohydrates) R-/S- Rightward (rectus)/leftward (sinister) arrange- ment of substituents about chiral center (modern, used for drugs) e.g., R-(-)- levorotatory, but with absolute configuration R 31

Assigning absolute configuration Sequence Rules for specification of Configuration (R & S Configuration)

(Cahn-Ingold-Prelog R/S system) Assignning Absolute Configuration (R) & (S) Configuration (Cahn-Ingold-Prelog R/S system) In the R,S system, groups are assigned priority using the Cahn-Ingold-Prelog system just as in the E,Z system for naming alkenes. To assign (R) or (S) configuration to a chiral carbon: 1. Rank the 4 atoms (groups) attached to the carbon . 2. Project the molecule so that the group (atom) of lowest priority is to the rear. The most probable atoms used are: H=1, C=6, N=7, O=8, F=9, S=16, Cl=17, Br=35 Br> Cl> S> F>O >N> C> H 3. Select the group (atom) of highest priority and draw a curved arrow toward the group (atom) of next lowest priority. (assign priority in order of decreasing atomic number). 4. Clockwise orientation (arrow direction) is R. Counterclockwise arrow direction is S. 33

A compound with n chiral carbon atoms can have a maximum of 2n stereoisomers. Example: a compound has 2 chiral carbons and 22 (= 4) stereoisomers. A compound with 3 chiral carbons and 23 (= 8) stereoisomers. Diastereomers Stereoisomers which are not mirror-image isomers are called diastereomers. Diastereomers have different chemical and physical properties. Diastereoomers: Possess > 1 chiral center Inversion of 1 chiral center produces a compound that is not a mirror image

DIASTEREOMERS

Meso Compounds A meso compound is an optically inactive compound even through it possesses more than one chiral centre. The two mirror Images of a meso Compound are Identical (superimposable).

One simple way of recognizing a meso compound is to note that the molecule possess a plane of symmetry (The upper half is the mirror image of its lower half in the previous example)

Fischer Projections Emil Fischer (late 1800's) introduced formulas depicting the spatial arrangement of groups around chiral carbon atoms. Fisher projection is the two-dimensional structure representation of stereochemical compound. A tetrahedral carbon atom is represented in a Fisher projection by two perpendicular lines. The intersection of horizontal and vertical lines (+) represents the chiral center The horizontal lines represent bonds coming out of the page (directed towards the reader) The vertical lines represent bonds going into the page (directed a way from the readers)

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Examples:

FISCHER PROJECTIONS AND THE EXCHANGE METHOD 1-To assign absolute R, S configuration to Fisher Projections 2-To compare sets of compounds to determine their stereochemical relationship (enantiomers, diastereomers, identical, or meso). 41

FISCHER PROJECTIONS AND THE EXCHANGE METHOD The R, S, configuration can be assigned by the following steps: Assign properties to four substituents in the usual way Perform one of the two allowed motions to place the group of lowest (fourth) priority at the top of the Fisher projection [ the single most important rule regarding rotation a Fischer is that 90° rotations are disallowed because rotating 90° generates the enantiomer of the molecule you started with. A 180° rotation regenerates the identical configuration, 270°an enantiomer, etc]. Determine the direction of rotation in going from priority 1 to 2 to 3. Draw a curved arrow toward the group (atom) of next lowest priority. Clockwise orientation (arrow direction) is R. Counterclockwise arrow direction is S. 42

I-Assigning priorities and determining R or S of compounds containing one chiral carbon

I-Assigning priorities and determining R or S of compounds containing one chiral acrbon It can then be done in the conventional manner. You should note, however, that in the drawing below, connecting the priorities in the original Fischer projection gives the same rotation as in the drawing on the right (both are S). This method will always work if the lowest priority group is oriented either up or down on your Fischer projection.

If the groups are oriented improperly in the original drawing, the Fischer can be “rearranged” using the following set of rules: 1-Exchanging any two groups around a Fischer projection ("one exchange") generates the enantiomer of the original compound, and 2-Exchanging groups twice ("two exchanges") regenerates the original stereochemistry.

In the example shown above, the original molecule (R configuration) is re-drawn with two of the groups "exchanged" so that the hydrogen (the lowest priority group) is placed in the "top" position; this new molecule now has S configuration. The second exchange regenerates the original R configuration. A third exchange would again generate S, a fourth, R, etc. An example of converting a drawing into a Fischer, and using it to assign configuration is shown below:

II-Assigning priorities and determining R or S of compounds containing multiple chiral carbons

For compounds with multiple chiral centers, written as extended Fischer projections, assignments can be made in the same manner, as shown below. In the following compound,

The top carbon is R, and, rearranging the bottom carbon, Enantiomer Identical

The "exchange method" can also be utilized to compare stereochemistry among Fischer projections by simply keeping track of the number of exchanges which are necessary to convert each chiral center into a reference structure.

I-The two molecules shown below are enantiomeric at both centers, and are therefore enantiomers.

II-The two molecules shown below are enantiomeric at one center, and identical at the other, and are therefore diastereomers.

III-The two molecules shown below are identical at one center, and identical at the other, and are therefore identical.

IV-The two molecules shown below are enantiomeric at both centers, and are therefore enantiomers, but one molecule can be seen to have an internal plane of symmetry, making this a meso compound. Since a meso compound is superimposible on its mirror image, the two molecules must be identical and meso.

Practice Problems

Q: Find the stereochemical relationship between the following two compounds Solution: These two compounds are constitutional isomers

Q: Find the stereochemical relationship between the following two compounds Solution: The two molecules differ in the stereochemistry of the alkene which is connected to the chiral center. But the two molecules, have the same bonding sequence (constitution) differing only in the arrangement of those atoms in space, making them stereoisomers. Since they are not enantiomeric, they must be diastereomers

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