kenapa perlunya mempelajari stereokimia? pharmacological activity of compounds(drugs) depend...

Kenapa perlunya mempelajari stereokimia?Kenapa perlunya mempelajari stereokimia?Pharmacological activity of compounds(drugs) depend mainly on Pharmacological activity of compounds(drugs) depend mainly on their interaction with biological matrices (drug targets), such astheir interaction with biological matrices (drug targets), such asproteins (receptors, enzymes), nucleic acids (DNA and RNA) and proteins (receptors, enzymes), nucleic acids (DNA and RNA) and biomembranes (phospholipids and glycolipids). biomembranes (phospholipids and glycolipids).

All these matrices have complex three-dimensional structures which All these matrices have complex three-dimensional structures which are capable to recognize (bind) specifically the ligand (drug) are capable to recognize (bind) specifically the ligand (drug) molecule in only one of the many possible arrangements in the molecule in only one of the many possible arrangements in the three-dimensional space. It is the three-dimensional structure of the three-dimensional space. It is the three-dimensional structure of the drug target that determines which of the potential drug candidate drug target that determines which of the potential drug candidate molecules is bound within its cavity and with what affinity. This molecules is bound within its cavity and with what affinity. This section concerns factors which control three-dimensional shape of section concerns factors which control three-dimensional shape of organic molecules (drugs) viewed from the perspective of their organic molecules (drugs) viewed from the perspective of their interaction with potential biological targets. interaction with potential biological targets.

StereokimiaStereokimia

Why is drug chirality an important knowledge for future pharmacists?Why is drug chirality an important knowledge for future pharmacists?

The current trend in drug markets is a rapid increase of the sales of The current trend in drug markets is a rapid increase of the sales of chiral drugs at the expense of the achiral ones. By the year 2000 chiral chiral drugs at the expense of the achiral ones. By the year 2000 chiral drugs, whether enantiomerically pure or sold as a racemic mixture, will drugs, whether enantiomerically pure or sold as a racemic mixture, will dominate drug markets. It is therefore important to understand how dominate drug markets. It is therefore important to understand how drug chirality affects its interaction with drug targets and to be able to drug chirality affects its interaction with drug targets and to be able to use proper nomenclature in describing the drugs themselves and the use proper nomenclature in describing the drugs themselves and the nature of forces responsible for those interactions. nature of forces responsible for those interactions. EXAMPLES OF DRUGS SOLD AS SINGLE ENANTIOMERS EXAMPLES OF DRUGS SOLD AS SINGLE ENANTIOMERS • Levomoprolol/Levotensin Levomoprolol/Levotensin • Levodropropizine/LevotussLevodropropizine/Levotuss• Levofloxacin/CravitLevofloxacin/Cravit• Barnidipine/HypocaBarnidipine/Hypoca• Dexfenfluramine/Isomeride Dexfenfluramine/Isomeride • Ibuprofen/SerectilIbuprofen/Serectil

StereokimiaStereokimia

The importance of most factors affecting the 3D-shape of the drug and The importance of most factors affecting the 3D-shape of the drug and receptor molecules is illustrated on the example of the oligopeptide receptor molecules is illustrated on the example of the oligopeptide chain above. Such an oligopeptide is a linear molecule which is built chain above. Such an oligopeptide is a linear molecule which is built by atoms separated from each other by a certain distance (bond by atoms separated from each other by a certain distance (bond length), endowed with a certain charge (due to bond polarity) or length), endowed with a certain charge (due to bond polarity) or hydrophobicity (a property of repelling water), related to more distant hydrophobicity (a property of repelling water), related to more distant sites in the molecules by a rotation angle about the single bond, and sites in the molecules by a rotation angle about the single bond, and featuring more rigid fragments such as bonds with partial double bond featuring more rigid fragments such as bonds with partial double bond characters. In addition, the orientation of the R group (amino acid side characters. In addition, the orientation of the R group (amino acid side chain) is very important (chirality of the amino acid), as it determines chain) is very important (chirality of the amino acid), as it determines the shape of the cavities lined with the oligopeptide chains. These the shape of the cavities lined with the oligopeptide chains. These factors are itemized below:factors are itemized below:

FACTORS THAT MAKE UP 3D-STRUCTURES OF RECEPTORS AND DRUGSFACTORS THAT MAKE UP 3D-STRUCTURES OF RECEPTORS AND DRUGS

STRUCTURESTRUCTURE is the complete arrangement of all the atoms of the is the complete arrangement of all the atoms of the molecule in space as determined by such methods as X-ray molecule in space as determined by such methods as X-ray diffraction (as defined by Cartesian coordinates of all atoms). This diffraction (as defined by Cartesian coordinates of all atoms). This terms is the broadest one and includes constitution (nature of terms is the broadest one and includes constitution (nature of atoms, their number, the type of bonds and manner in which they atoms, their number, the type of bonds and manner in which they are linked together(connectivity)), conformation and configuration. are linked together(connectivity)), conformation and configuration.

CONFORMATIONCONFORMATION is the spatial arrangement of atoms in the molecule is the spatial arrangement of atoms in the molecule of the given constitution and configuration. Conformation can be of the given constitution and configuration. Conformation can be changed without changes in constitution and configuration by a changed without changes in constitution and configuration by a rapid(?) rotation about single bonds and pyramidal inversion(?) at rapid(?) rotation about single bonds and pyramidal inversion(?) at some centers. some centers.

CONFIGURATIONCONFIGURATION is the spatial arrangement of atoms that is the spatial arrangement of atoms that distinguishes molecules of the same constitution (isomers), other distinguishes molecules of the same constitution (isomers), other than distinction due to differences in the conformation. than distinction due to differences in the conformation.

SYMMETRYSYMMETRY is a regular occurrence of certain patterns within an object is a regular occurrence of certain patterns within an object or structure (at macro- or microscopic level). These patterns are or structure (at macro- or microscopic level). These patterns are generated by the presence of symmetry elements such as center of generated by the presence of symmetry elements such as center of symmetry; symmetry axes; symmetry planes.symmetry; symmetry axes; symmetry planes.

GLOSSARY OF TERMS RELATED TO 3D-STRUCTURE OF MOLECULESGLOSSARY OF TERMS RELATED TO 3D-STRUCTURE OF MOLECULES

CHIRALITYCHIRALITY is a property of an object which is non-superimposable with its is a property of an object which is non-superimposable with its mirror image. Most objects in the environment are chiral. In chemistry this mirror image. Most objects in the environment are chiral. In chemistry this term applies to molecules, specific conformations of molecules, as well as to term applies to molecules, specific conformations of molecules, as well as to macros copic objects such as crystals. Chirality is removed if and object macros copic objects such as crystals. Chirality is removed if and object molecule acquires a plane of symmetry, or a center of symmetry. The molecule molecule acquires a plane of symmetry, or a center of symmetry. The molecule can remain chiral with a limited combination of symmetry axes. can remain chiral with a limited combination of symmetry axes.

ENANTIOMERSENANTIOMERS are molecules related to each other as a real object to its mirror are molecules related to each other as a real object to its mirror image. Enantiomers are therefore related to each other through the reflection image. Enantiomers are therefore related to each other through the reflection by the mirror plane, and are not superposable. Not all object/mirror-image by the mirror plane, and are not superposable. Not all object/mirror-image pairs constitute enantiomers, but only those which are not superimposable pairs constitute enantiomers, but only those which are not superimposable after any rotation/translation of the whole object, or its mirror image. after any rotation/translation of the whole object, or its mirror image. Enantiomeric relation does not bear the aspect of energy; the conformational Enantiomeric relation does not bear the aspect of energy; the conformational isomers existing in the fast interconversion are still considered enantiomers. isomers existing in the fast interconversion are still considered enantiomers. For the purpose of the determination whether two conformations are For the purpose of the determination whether two conformations are enantiomeric, they are considered to be rigid. The existence of enantiomers is enantiomeric, they are considered to be rigid. The existence of enantiomers is usually (but not always) associated with at least one chiral center. usually (but not always) associated with at least one chiral center. Enantiomers have exactly the same energies, and therefore are not Enantiomers have exactly the same energies, and therefore are not differentiated by physical measurements other than optical rotation (rotation of differentiated by physical measurements other than optical rotation (rotation of the plane of polarized light). the plane of polarized light).


DIASTEREOMERSDIASTEREOMERS are any molecules which have an identical are any molecules which have an identical constitution, but are not related through the mirror reflection constitution, but are not related through the mirror reflection operation. Diastereomers could be compounds with two or more operation. Diastereomers could be compounds with two or more chiral centers, in which not all chiral centers have opposite chiral centers, in which not all chiral centers have opposite configuration to a corresponding chiral centers in another molecule configuration to a corresponding chiral centers in another molecule (the whole molecule would be the mirror image of the other and thus (the whole molecule would be the mirror image of the other and thus an enantiomer). Diastereomers do not have to possess chiral an enantiomer). Diastereomers do not have to possess chiral center(s), they only need to differ by a spatial difference not related center(s), they only need to differ by a spatial difference not related to mirror reflection. Thus, diastereomers could be nonchiral to mirror reflection. Thus, diastereomers could be nonchiral cis/transcis/trans -isomers of cyclic or olefinic (alkene) compounds. Diastereomers and -isomers of cyclic or olefinic (alkene) compounds. Diastereomers and enantiomers are frequently jointly referred to as stereoisomers. enantiomers are frequently jointly referred to as stereoisomers.

STEREOISOMERS:STEREOISOMERS: a combined term including enantiomers and a combined term including enantiomers and diastereomersdiastereomers


1. Center of Symmetry1. Center of SymmetryThe center of symmetry The center of symmetry ii is a point in space such that if a line is drawn is a point in space such that if a line is drawn from any part (atom) of the molecule to that point and extended an equal from any part (atom) of the molecule to that point and extended an equal distance beyond it, an analogous part (atom) will be encountered. distance beyond it, an analogous part (atom) will be encountered. This symmetry element is sometimes also called "the point of inversion" This symmetry element is sometimes also called "the point of inversion"

SYMMETRY ELEMENTSSYMMETRY ELEMENTS

2. Plane of SymmetryPlanes, centers and alternating axes correspond to "symmetry operations of

the second kind" or "improper operations" since they bring into coincidence the material point of an object with its mirror reflection.

A plane of symmetry is a reflection plane which brings into coincidence one point of the molecule with another one through the mirror reflection.


3. Axis of SymmetrySymmetry axis Cn, also called n-fold axis, is an axis which rotates the object (molecule) around by 360ø/n, such that the new position of an object is superimposable with the original one.


Fisher projection:The tetrahedral atom

is viewed

perpendicularly to an edge formed by connecting two of its ligands. The

convention is that the two

vertical bonds in the

projection are pointing behind

the plane of projection (plane of paper

sheet), and the two

horizontal bonds are pointing towards the viewer.

GRAPHICAL REPRESENTATION OF NONPLANAR MOLECULESGRAPHICAL REPRESENTATION OF NONPLANAR MOLECULES

It is obtained by viewing the tetrahedral center perpendicularly to the plane formed

by three atoms. One of the remaining atoms is oriented behind the plane of projection

(dashed bond), one towards the viewer (boldface bond). Note that, in contrast to

Fisher projection, the rotation of the wedge projection about axes perpendicular or

coplanar with the plane of projection does not change anything. This projection is

therefore by far less ambiguous than Fisher projection. In the case of large linear

molecule the molecule backbone has to be drawn in the fully extended conformation.

Wedge projectionWedge projection

The molecule with two tetrahedral centers is viewed along the C-C axis.

The atom in front is represented as a three-way branch, the atom in the

back as a circle with three outgoing bonds. This projection is most useful

inconsideration of steric relation between ligands linked to adjacent

tetrahedral centers and is most popular.

.

Newman projectionNewman projection:

The C-C bond is viewed at an angle. The atom shown on the left of the

projection is also the one in the front. This projection is difficult to use

with acyclic molecules but is most popular for representation of cyclic

molecules e.g. saturated six-membered rings .

.

Sawhorse projection:Sawhorse projection:

.

Haworth projection:Haworth projection:

INTERACTION OF DRUGS WITH BIOLOGICAL INTERACTION OF DRUGS WITH BIOLOGICAL MATRICESMATRICES

Chirality (enantiomerism)It is very important from the point of view of drug

development and its mechanism of action. Since most of the natural

(biological) environment consists of enantiomeric molecules

(aminoacids, nucleosides, carbohydrates and phospholipids are chiral

molecules) it makes sense that drugs developed are also chiral. Frequently only one stereoisomer is active, and sometimes

the other one is toxic (the current policies of FDA in drug approval is

that the inactive enantiomer in the racemic drug has to be shown to

be devoid of any toxicity or undesired side-effects). A drug upon administration undergoes a series of steps

before exerting its activity. At each step the structure of the drug

and hence its chirality influences the further metabolism


.


The reason for chiral recognition by drug receptors is a three-point interaction of the agonist or substrate with the receptor or enzyme

active site, respectively.

.


Example: Only the (-) enantiomer of epinephrine has the OH group in the

binding site, and therefore has a much more potent pressor activity

.


The D(-) lactoyl choline is hydrolyzed much more slowly than the L(+)-isomer due to favorable binding of the OH group in the latter case.

.


Likewise, cis/trans isomers of cyclic compounds, or Z/E isomers of alkenes are also expected to have different binding potency and therefore also different biological activity.

.

RULES FOR SPECIFICATION OF CHIRALITYRULES FOR SPECIFICATION OF CHIRALITY1. Chiroptical properties1. Chiroptical properties

Any material which rotates the plane of the polarized light is termed "optically

active." Compounds featuring chiral centers are optically active unless they

possess symmetry plane or a symmetry center (see above). An isomer of optically active compound can rotate the plane of polarized light to the left (levorotatory), in which case it will be designated (l, or -), or to the right (dextrorotatory) in which case it will be termed (d, or +). There are following properties associated with enantiomerism: 1. Enantiomeric molecules interact in a different manner with another

enantiomeric molecules (such as biological receptors, but also with simple chiral organic molecules); it regards both weak interaction such as forming weak complexes, as well as chemical reactions (bond breaking or forming).

2. Enantiomers can not be distinguished by their interactions with achiral molecules, nor by their physical properties measured by techniques other than those using in-plane-, or circularly-polarized light.

1. Chiroptical properties1. Chiroptical properties

Several rules for specifying chirality have been adopted from the time of van't Hoff. The L/D systems relies on the chemical correlation of the configuration of the chiral center to D-glyceraldehyde. The compounds which can be correlated without inverting the chiral center are named D (capital D), those correlated to its enantiomer are designated as L (capital L).

IMPORTANT NOTE: Although D-glyceraldehyde is dextrorotatory (rotates the plane of polarized light to the right), the compounds correlated to D-glyceraldehyde do not have to be dextrorotatory, i.e. could rotate light to the left. Therefore, D-prefix is not correlated with the (+) or (-) specific rotation, and the D-compound can be l, (or -), and vice versa L-compound can be d (or +). This nomenclature system is slowly being abandoned in favor of the Cahn-Ingold-Prelog (CIP) nomenclature, with the exception where the DL-nomenclature has been used traditionally, and is more useful (D-carbohydrates or L-aminoacids).

1. Chiroptical properties1. Chiroptical properties

EXAMPLE:An antiinflammatory agent such as Ibuprofen has two configurations(R and S). However, only S-configuration has pharmacologic properties. The demonstration(video) of superposition between the S and R

configurations indicates that they are enantiomers. They are nonsuperposable mirror reflection of each other

2. Cahn-Ingold-Prelog Rules2. Cahn-Ingold-Prelog Rules

For the tetrahedral chiral center C with four inequivalent substituents the rule is adopted for designation of chirality.

• First ligands are ordered by the ligand precedence rules as 1,2,3 & 4. • The central atom and three ligands are viewed from the direction of C 4

vector where 4 is a ligand of lowest precedence. • If the ligands 1-3 are ordered such that the movement from the ligand of the

highest precedence (1) to the third (3) passing the second (2) in between is in the clockwise direction (sequence 1 2 3) the configuration is designated as R (rectus, written in italic, capital). On the other hand if the same requires movement in the anti clockwise direction the configuration is designated as S (sinister). The configurational designation is preceded by the number specifying the location of the chiral center, i.e. 2R with one chiral center at the 2-position and R configuration, or 2R, 3S, 4R with multiple chiral centers.

3. Ligand precedence rules3. Ligand precedence rules

Ligands of the higher atomic number precede those with lower ones, e.g. Br precedes Cl (Br>Cl).

1. For ligands with the same type of atoms linked to the center C, the precedence is determined based on the atomic numbers of ligands in the next sphere, e.g. ligand with C-O sequence precedes C-C. If no difference is detected, the determination is based on the distinction in the next spheres, and search is continued until the difference is detected.

2. The coordination number of non-hydrogen atoms is assumed to be 4, i.e. atoms bonded with multiple bonds are considered to be bonded to multiple atoms, e.g. carbonyl carbon is treated as if it was bonded to two oxygen atoms, and carboxyl carbon as if it was bonded to three oxygens (these are then called phantom atoms). Ligand duplication is also necessary in the cases of cyclic systems

3. Ligands of the same atomic number, but a higher atomic mass precede those with a lower atomic mass, e.g. D precedes H (D>H). This criterion applies only after the previous ones were exhausted.

4. For compounds where only configurational (not constitutional) differences between ligands are detected, the following rules apply:

• The olefinic ligand that has the chiral center and another ligand on the same side of the double bond (cis) precedes the one with the trans-configuration.

• Ligands with R,R or S,S precede R,S or S,R. • R precedes S

3. Ligand precedence rules3. Ligand precedence rules

.

4. Helical Chirality4. Helical Chirality

Certain natural, as well as unnatural linear polymers assume helical conformation: e.g.

right-handed B-DNA, left-handed Z-DNA, protein alpha-helices. The hydrated lipids

can form chiral mesophases, whereby chirality is due to small rotation of each layer

versus the adjacent layers in the multilayer stack. These macromolecules or aggregates

are said to have helical chirality. The chirality of such compounds is determined by determining the screw

sense of the helix. If the screw is right handed the chirality is P(plus), if it is left handed the

chirality is M(minus). Conformations of simple chain compounds can also be treated

as if they had helical chirality

5. Z/E Geometry of Double Bonds5. Z/E Geometry of Double Bonds

The same Prelog's precedence rules, as discussed earlier, apply to geometrical isomers of olefinic compounds and alicyclic compounds. Precedence of ligands at both nodes of the double bonds is determined pairwise. If both higher precedence ligands are on the same side of the double bond the configuration is Z, if on the opposite sides the configuration is E.

6. cis/trans Geometry of Alicyclic Compounds6. cis/trans Geometry of Alicyclic Compounds

The cyclic systems use the traditional cis/trans nomenclature. When specifying geometry (cis/trans) the precedence of substituents is also determined based on the precedence rules set forth earlier. The situation is simple in the case of disubstituted systems, however, in the case of multiple substitution the geometry of the ring system has to be specified with respect to a selected reference indicated by the the symbol "r" (italic). Example:

7. Relative Configurations in Compounds with Multiple Chiral Centers.

The most unambiguous notation employs Prelog's descriptors R,S. For

example for D-glucose (below) the correct specification of chirality is 2R, 3S,

4R, 5S. Note that only R,S descriptors are italicized and the chirality is

specified with the numerical prefix denoting this position. The configuration of racemic compounds is specified by using RS

notation for each chiral center. Note that the relative configurations have to be

preserved in order to correspond to a given diastereomers Thus racemic

glucose would be described as 2RS, 3SR, 4RS, 5SR. (in contrast, 2SR, 3SR, 4RS,

5SR would correspond to racemic mannose).

7. Relative Configurations in Compounds with Multiple Chiral Centers.

The use of CIP nomenclature requires assignment of R,S descriptors for every center. The quicker way (older and a more ambiguous one) is by using threo/erythro nomenclature. This notation is based on the four-carbon sugars threose and erythrose. It requires vertical projection of the sugar main chain; threo-compounds are defined as those that have two ligands of higher precedence on each carbon atom on the opposite sides of the chain, erythro on the same side. The ambiguity arises from the question what should be used as the main chain

8. Mezo Compounds and Pseudoasymmetry8. Mezo Compounds and Pseudoasymmetry

In compounds in which two or more chiral

ligands of the central atom are constitu-tionally identical but have the opposite configuration the central atom is

formally chiral because it has four different

ligands (even though the difference is only in

ligand configuration). However, since such a compound also has a plane of symmetry

it is, in fact, achiral as a whole. The central

atom is termed a pseudoasymmetric center.

The configuration of such atom is

determined according to normal precedence rules assuming that R precedes S. In contrast,

in molecules in which the two ligands of

the central atom havethe same

configuration the central atom is achiral, but the molecule

as a whole is chiral. The pseudoa -symmetry

can also exist with chiral axes instead of

centers. The chirality of a pseudoasymmetric

carbon is specified with the lower case r/s descriptors.

CONFORMATIONCONFORMATION

DEFINITIONConformation is a spatial arrangement of a molecule of a given constitution and

configuration. In the case of a four atom molecule linked in a chain manner, rotation of atom A or D

about the inner B-C bond by an angle leads to a different mutual relation of atom A and D and

results in population of a set of different rotational isomers or "conformations".

The single parameter differentiating such conformers is an angle between two planes that

contain atoms ABC and BCD in themselves. This dihedral angle is called a "torsion" angle

and is most frequently used for specification of the type of conformations.

The conformation of a molecule containing two tetrahedral atoms linked together can be represented as a "sawhorse" or as a Newman projections. In the Newman projection the molecule is viewed along the axis of a rotatable bond.

..

IsomersIsomers

1. STRUCTURAL ISOMERISM1. STRUCTURAL ISOMERISMa. Chain isomerisma. Chain isomerismb. Position isomerism b. Position isomerism c. Functional group isomerismc. Functional group isomerism

2. STEREOISOMERS2. STEREOISOMERSa. Enantiomera. Enantiomer

- - atropisomeratropisomerb. Diastereomersb. Diastereomers

- Two or more sterocentre- Two or more sterocentre- - Geometric (cis / trans) isomerismGeometric (cis / trans) isomerism

IsomersIsomers

How geometric isomers ariseHow geometric isomers ariseTo get geometric isomers you must have:To get geometric isomers you must have:• restricted rotation restricted rotation

(involving a carbon-carbon double bond)(involving a carbon-carbon double bond)• two different groups on the left-hand end of the bond two different groups on the left-hand end of the bond

and two different groups on the right-hand end. and two different groups on the right-hand end. It doesn't matter whether the left-hand groups are It doesn't matter whether the left-hand groups are the same as the right-hand ones or not.the same as the right-hand ones or not.

Geometric (cis / trans) isomerismGeometric (cis / trans) isomerism

The effect of geometric isomerism on physical propertiesThe effect of geometric isomerism on physical properties• The table shows the melting point and boiling point The table shows the melting point and boiling point

of the cis and trans isomers of 1,2-dichloroethene.of the cis and trans isomers of 1,2-dichloroethene.

• The trans isomer has the higher melting point;the cis isomer has The trans isomer has the higher melting point;the cis isomer has the higher boiling point.the higher boiling point.

• Both of the isomers have exactly the same atoms joined up in Both of the isomers have exactly the same atoms joined up in exactly the same order. That means that the van der Waals exactly the same order. That means that the van der Waals dispersion forces between the molecules will be identical in both dispersion forces between the molecules will be identical in both cases.The difference between the two is that the cis isomer is a cases.The difference between the two is that the cis isomer is a polar molecule whereas the trans isomer is non-polar.polar molecule whereas the trans isomer is non-polar.


IsomersIsomers Melting point (Melting point (00C)C) Boiling point(Boiling point(00C)C)CisCis -80-80 6060

TransTrans -50-50 4848

• Both of the isomers have exactly the same atoms joined up in Both of the isomers have exactly the same atoms joined up in exactly the same order. That means that the van der Waals exactly the same order. That means that the van der Waals dispersion forces between the molecules will be identical in dispersion forces between the molecules will be identical in both cases.The difference between the two is that the cis both cases.The difference between the two is that the cis isomer is a polar molecule whereas the trans isomer is non-isomer is a polar molecule whereas the trans isomer is non-polar.polar.

• Both molecules contain polar chlorine-carbon bonds, but in Both molecules contain polar chlorine-carbon bonds, but in the cis isomer they are both on the same side of the molecule. the cis isomer they are both on the same side of the molecule. That means that one side of the molecule will have a slight That means that one side of the molecule will have a slight negative charge while the other is slightly positive. The negative charge while the other is slightly positive. The molecule is therefore polar.molecule is therefore polar.

• Because of this, there will be dipole-dipole interactions as well Because of this, there will be dipole-dipole interactions as well as dispersion forces - needing extra energy to break. That will as dispersion forces - needing extra energy to break. That will raise the boiling pointraise the boiling point


Enantiomers: Enantiomers: A mixture of these cannot be separated by normal GC or HPLC A mixture of these cannot be separated by normal GC or HPLC

techniquestechniques

Diastereomers:Diastereomers:Different physical/chemical properties in chiral/achiral environments. Different physical/chemical properties in chiral/achiral environments.

A mixture of these can be separated by normal GC or HPLC A mixture of these can be separated by normal GC or HPLC techniquestechniques


Stereogenic center (stereocenterStereogenic center (stereocenter) –) – a point in a molecule bearing groups such that an interchange of any two groups will a point in a molecule bearing groups such that an interchange of any two groups will

produce a stereoisomer. Number of possible stereoisomers = 2produce a stereoisomer. Number of possible stereoisomers = 2n , n = # of stereocenters.n , n = # of stereocenters.

Relative vs. Absolute ConfigurationsRelative vs. Absolute Configurations• Relative configuration - 3-D structure is not known but it is known that one structure Relative configuration - 3-D structure is not known but it is known that one structure

is the mirror image of the other.is the mirror image of the other.• (+) or (+) or dd - dextrorotatory - cpd that rotates light to the right. - dextrorotatory - cpd that rotates light to the right.• (-) or (-) or ll - levorotatory - cpd that rotates light to the left. - levorotatory - cpd that rotates light to the left.• (±) - racemic mixture - 1:1 mixture of (+) and (-) cpds, zero rotation.(±) - racemic mixture - 1:1 mixture of (+) and (-) cpds, zero rotation.• Enantiomeric excess:Enantiomeric excess:

• Absolute configuration - 3-D structure is known.Absolute configuration - 3-D structure is known.


(-)-alanine(-)-alanine

1.1. Prioritize - assign a priority to the groups around the stereocenterPrioritize - assign a priority to the groups around the stereocentera.a. increasing atomic mass of the atom attached to stereocenter increasing atomic mass of the atom attached to stereocenter b.b. in case of a tie move to the next atomin case of a tie move to the next atom2. Place - place the lowest priority group in the back. 2. Place - place the lowest priority group in the back. 3.3. Connect a Connect a b b c c

R, S NomenclatureR, S Nomenclature

A)A) ResolutionResolution

B)B) Pasteur's MethodPasteur's Method

Separation of EnantiomersSeparation of Enantiomers

kenapa perlunya mempelajari stereokimia? pharmacological activity of compounds(drugs) depend...

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