Chapter 1 Stereochemistry PDF - King Khalid University

King khalid University College of Science Department of Chemistry Chapter 1 Stereochemistry Prof. Ahmed Fouda 1446 Course general Description This course is designed to cover sele...

King khalid University College of Science Department of Chemistry Chapter 1 Stereochemistry Prof. Ahmed Fouda 1446 Course general Description This course is designed to cover selected topics in advanced organic chemistry. The suggested topics might be stereochemistry, polymers and industry products, natural products, chemistry of carbohydrates and cellulose, physical organic chemistry, and petrochemicals and detergents. Course Main Objective The main objective of this course is to provide students with advanced knowledge and skills in one or more of the selected topics mentioned above. This course can be taught by the thesis supervisors who will choose the topics according to the thesis research project or by other staff and another topic from the suggested topics. The topic (s) will be chosen periodically and according to the recent trends and relevant results in the scientific research related to the organic chemistry. Students Assessment Activities Assessment timing Percentage of Total Assessment Activities (in week no) Assessment Score Midterm Exam 6th 25% Oral discussion Continues 10% Presentation 7-9th 10% Seen Exam (homework) 3-9th 5% Final Exam 13th 50% Total 100% Stereochemistry is the branch of science that deals with the study of three dimensions structure, reactions, and properties of given molecules. ❑ The physical, Chemical, and biological properties of the molecule depend upon the stereochemistry i.e. the position of atoms within the molecule. ❑ Compounds having the same molecular formula, but different structures are known as Isomers and this phenomenon is known as Isomerism. A - Structural Isomerism Possess the same molecular formula but different structural formula i.e. they have different IUPAC names, the same or different function groups, different physical and chemical properties. 1) Chain Isomerism. Exists when two or more compounds have the same molecular formula, but the way their carbon atoms are joined together differs from isomer to isomer. The formula C4H10 represents two possible structural formulae, n-butane and methyl propane (iso-butane) C5H12 C7H16 2) Positional Isomerism Exists when two or more compounds have the same carbon skeleton and the same functional groups but differ from each other in the location of the functional groups on or in the carbon chain. C 3 H6 O C2H4Br2 C3H6Br2 3) Functional Group Isomerism Exists when two or more compounds having the same molecular formula but different functional groups. C 2 H6 O C 3 H6 O C 3 H6 O 2 4) Metamerism Exists when two or more compounds having the same molecular formula but the different number of carbon atoms around the functional group. Diethyl ether, methyl n-propyl ether, and methyl isopropyl ether are metamers. Since all of them have the same molecular formula (C4H10O) but the groups are different. 5) Tautomerism It is a dynamic isomerism where one isomer is constantly changing into the other and vice versa. This is a special case of functional isomerism. Alkyl cyanides (RCN) and alkyl isocyanides (RNC) are also tautomers. 6) Rind/Double bond isomers Such type of isomers exists between ring/cyclic structure (like cycloalkanes) and acyclic alkene since both have the same molecular formula i.e. CnH2n. B- Stereoisomerism Stereoisomers are compounds have the same structure and bond order, but their atoms and groups of atoms are arranged differently in space. They have different spatial arrangements, and their molecules are not superimposable. There are two types: Conformational isomers ❑ These are stereoisomerism that can be interconverted just by rotations about formally single bonds. ❑ The different arrangements of atoms within a molecule due to rotation about a single bond are known as conformers/Rotamers. Configurational isomers: ❑ Configurational isomerism is a type of stereoisomerism where the isomers have the same molecular formula and connectivity of atoms but differ in the spatial arrangement of their atoms. ❑ This difference in arrangement cannot be interconverted by simple rotation around single bonds, which distinguishes configurational isomers from conformational isomers. Geometric isomers These isomers occur where you have restricted rotation somewhere in a molecule. Cis – Trans & E – Z ❑ Compounds in which rotation is restricted may exhibit cis-trans isomerism. ❑ The term Cis – Trans is derived from the Latin, in which cis means “on the same side” and trans means “on the other side” ❑ These compounds do not rotate the plane of polarized light (unless they also happen to be chiral), and the properties of the isomers are not identical. ❑ For a molecule WXC=CYZ, stereoisomerism exists when W≠X and Y≠Z. ❑ There are two and only two isomers each superimposable on its mirror image unless one of the groups happens to carry a stereogenic center. In the older method, these isomers are called cis and trans. ❑ When the four groups are different it will not be easy to apply this method. The newer method, which can be applied to all cases, is based on the Cahn–Ingold–Prelog system. ❑ The two groups at each carbon are ranked by the sequence rules. ❑ Then that isomer with the two higher ranking groups on the same side of the double bond is called (Z) (for the German word zusammen meaning together); the other is (E) (for entgegen meaning opposite). ❑ Like cis and trans, (E) and (Z) are used as prefixes. ❑ If one of the two carbon atoms of the double bond has two identical substituents, then there are no cis– trans isomers for that molecule. Physical properties of geometrical isomers ❑ Trans isomers have higher melting points than the corresponding cis isomers as the former is more symmetrical and fits well into the crystal structure. ❑ Cis isomers have higher boiling point than the corresponding trans isomers because of stronger intermolecular forces between the molecules of the cis isomers than the trans isomers. ❑ Dipole Moment: Generally Cis isomers have greatest dipole moment than trans isomers with some exceptions. Optical Isomerism Optical Activity and Chirality Optical activity: The ability of a molecule to rotate the path of plane polarized light. ❑ Any compound that rotates the plane of polarized light is said to be optically active. ❑ If a pure compound is optically active, the molecule is nonsuperimposable on its mirror image. ❑ If a molecule is superimposable on its mirror image, the compound does not rotate the plane of polarized light; it is optically inactive. Plane polarized light Light that has been passed through a Nicol prism or other polarizing medium so that all the vibrations are in the same plane. Plane polarized light through a Chiral compound. Polarimeter An instrument used to measure optical activity. A simple polarimeter consists of a light source, polarizing lens, sample tube, and analyzer Specific Rotation    = Τ λ lxc T is the temp in °C  is the wavelength α is the measured rotation in degrees l is the path length in decimeters C is the concentration in gram per mL ❑ Each optically active compound has a characteristic specific rotation. Dextrorotatory (+) An optically active compound that rotates plane polarized light in clockwise direction. It is represented by (+) or (d). Levorotatory (-) An optically active compound that rotates plane polarized light in counterclockwise direction. It is represented by (-) or (I). Dependence of Rotation on Conditions of Measurement ❑ The amount of rotation α is not a constant for a given enantiomer; it depends on the length of the sample vessel, the temperature, the solvent and concentration (for solutions), the pressure (for gases), and the wavelength of light. ❑ Rotations determined for the same compound under the same conditions are identical. The Reason of Optical Activity ❑ Whenever any light hits any molecule in a transparent material, the light is slowed because of interaction with the molecule. ❑ On a large scale, this phenomenon is responsible for the refraction of light, and the decrease in velocity is proportional to the refractive index of the material. ❑ The extent of interaction depends on the polarizability of the molecule. ❑ Plane-polarized light may be regarded as being made up of two kinds of circularly polarized light. ❑ Circularly polarized light has the appearance of a helix propagating around the axis of light motion, one kind is a left-handed helix and the other is a right-handed helix. ❑ As long as the plane-polarized light passes through a symmetrical region, the two circularly polarized components travel simultaneously. ❑ A chiral molecule has a different polarizability depending on whether it is approached from the left or the right. One circularly polarized component approaches the molecule from the left and sees a different polarizability than the other and is slowed to a different extent. ❑ The left- and right-handed circularly polarized components travel at different velocities since each has been slowed to a different extent. ❑ However, it is not possible for two components of the same light to be traveling at different velocities. ❑ What takes place, therefore, is that the faster component ‘‘pulls’’ the other toward it, resulting in the rotation of the plane. Chirality ❑ The term chiral, from the Greek word for 'hand', refers to anything which cannot be superimposed on its mirror image. ❑ Certain organic molecules are chiral meaning that they are not superimposable on their mirror image. ❑ Chiral molecules contain one or more chiral centers. ❑ Asymmetric (Chiral) center–tetrahedral atom bonded to four different groups indicated with an asterisk (*). For compound A and B, every point on A lines up through the mirror with the same point on B. ❑ Upon turning compound A over and attempting to overlay it point-for-point on compound B, we discover that this is not possible: if we line any two colored balls on top of each other, the other two will be out of alignment. ❑ Since A cannot be superimposed on its mirror image (B), it is a chiral molecule. ❑ B is likewise a chiral molecule since it cannot be superimposable on its mirror image, A. ❑ A and B are called stereoisomers or optical isomers Optical isomers: molecules with the same molecular formula and the same bonding arrangement, but a different arrangement of atoms in space. Creation of a Stereogenic Center Any structural feature of a molecule that gives rise to optical activity may be called a stereogenic center (the older term is chiral center) In many reactions, a new chiral center is created. Enantiomers: Enantiomers are pairs of stereoisomers which are mirror images of each other. Enantiomers are related to each other as a right hand is related to a left hand and result whenever a carbon is bonded to four different substituents. ❑ The compound and its mirror image are said to be a pair of enantiomers. ❑ Enantiomers differ in their configuration (R or S) at the stereogenic center. ❑ Enantiomers rotate the direction of plane polarized light to equal, but opposite angles and interact with other chiral molecules differently. ❑ A mixture of enantiomers in equal proportions is optically inactive and is called a racemic mixture. ❑ A molecule with 1 chiral carbon atom exists as 2 stereoisomers termed enantiomers. ❑ Enantiomers have identical physical properties (melting point, boiling point, density, and so on) and chemical properties. Naming Enantiomers The R,S system of nomenclature The method of unambiguously assigning the handedness of molecules was originated by three chemists: R.S. Cahn, C. Ingold, and V. Prelog, and is also often called the Cahn-Ingold-Prelog rules. ❑ Rank the groups (atoms) bonded to the chirality center and Orient the lowest priority (4) away from you. Consider the following arrangement: ❑ A curved arrow is drawn from the highest priority (1) substituent to the lowest priority (4) substituent. ❑ If the arrow points in a counterclockwise direction, the configuration at the stereocenter is considered S ("Sinister" → Latin= "left"). Consider the following arrangement: ❑ The arrow points clockwise, then the stereocenter is labeled R ("Rectus" → Latin= "right"). ❑ The R or S is then added as a prefix, in parenthesis, to the name of the enantiomer of interest. Diastereomers: ❑ Diastereomers are two molecules that are stereoisomers (same molecular formula, same connectivity, different arrangement of atoms in space) but are not enantiomers. ❑ Diastereomers are not mirror representations of each other, in contrast to enantiomers, which are mirror images of each other. ❑ why cis-trans isomers are said to be diastereomers, rather than enantiomers? ❑ Diastereomers can have different physical properties (different melting, boiling points, and different densities) and reactivity. ❑ In order for diastereomer stereoisomers to occur, a compound must have two or more stereocenters. ❑ Since we used the right-hand/left-hand analogy to describe the relationship between two enantiomers, we might extend the analogy by saying that the relationship between diastereomers is like that of hands from different people. ❑ Your hand and your friend’s hand look similar, but they aren’t identical, and they aren’t mirror images. The same is true of diastereomers: they’re similar, but they aren’t identical, and they aren’t mirror images. ❑ As a general rule, a molecule with n chirality centers can have up to 2n stereoisomers (although it may have fewer). Stereoisomers of 2-amino-3-hydroxybutanoic acid (Threonine) ❑ The stereoisomers of 2-amino-3-hydroxybutanoic acid can be grouped into two pairs of enantiomers. ✓ The 2R,3R stereoisomer is the mirror image of 2S,3S. ✓ The 2R,3S stereoisomer is the mirror image of 2S,3R. Relationships among the Four Stereoisomers of Threonine Stereoisomer Enantiomer Diastereomer 2R,3R 2S,3S 2R,3S and 2S,3R 2S,3S 2R,3R 2R,3S and 2S,3R 2R,3S 2S,3R 2R,3R and 2S,3S 2S,3R 2R,3S 2R,3R and 2S,3S Stereoisomers of Ephidrine Properties of four stereoisomers of Ephidrine R, R S, S R, S S, R Melting range (oC) 117 - 118 117 - 118 40 - 41 40 - 41 Optical rotation (o) -52.1 +52.1 -6.3 +6.3 ❑ Enantiomers have identical chemical and physical properties in an achiral environment. ❑ Diastereomers have different chemical and physical properties (melting range, solubility, etc.) Epimers ❑ If the two diastereomers differ at only one chirality center but are the same at all others, we say that the compounds are epimers. ❑ Cholestanol and coprostanol, are both found in human feces, and both have nine chirality centers. Eight of the nine are identical, but the one at C5 is different. Thus, cholestanol and coprostanol are epimeric at C5. Fischer projection ❑ The Fischer Projections allow us to represent 3D molecular structures (stereoformula) in a 2D environment without changing their properties and/or structural integrity (stereochemical information). ▪ Fischer projection represents an asymmetric carbon as the point of intersection of two perpendicular lines:- ✓ Horizontal lines represent the bonds that project out of the plane of the paper toward the viewer. ✓ Vertical lines represent the bonds that extend back from the plane of the paper away from the viewer. The carbon chain always is drawn vertically with C-1 at the top of the chain.  A B Notice: 1) The atoms represented with red balls in Figure A, are pointing away from the screen. Numbers 2 and 6 will indicate these atoms with dashed lines similar to those in Figure B. 2) The atoms represented by the green balls, are pointed toward the screen. Numbers 3 and 5, these atoms will be designated with wedged lines like those in Figure B. 3) The blue atoms are in the screen's plane, they are indicated as straight lines. How to convert the stereoformula into a Fischer projection Step 1: Hold the molecule so that: ✓ The chiral center is on the plane of the paper, ✓ The two bonds are coming out of the plane of the paper and are on a horizontal plane, ✓ The two remaining bonds are going into the plane of the paper and are on a vertical plane. Step 2: Push the two bonds coming out of the plane of the paper onto the plane of the paper. Step 3: Pull the two bonds going into the plane of the paper onto the plane of the paper. Step 4: Omit the chiral atom symbol for convenience. i.e. 1) Fischer Projection Structure of (R)-(+)-glycerladehyde 2) Fischer Projection Structure of (R) – Lactic acid 3) Fischer Projection Structure of Therose Detection of the absolute configuration of a chiral center in a Fisher projection Step 1: Assign priority numbers to the four ligands on the chiral center. (see R,S convention). Step 2: a) If the lowest priority ligand is on a vertical bond, meaning that it is pointing away from the viewer, trace the three highest-priority ligands starting at the highest-priority ligand (1 2 3). Direction 1 2 3 Absolute configuration Clockwise R Counterclockwise S b) If the lowest-priority ligand is on a horizontal bond, meaning that it is pointing toward the viewer, trace the three highest-priority ligands starting at the highest-priority ligand (1 2 3). Direction 1 2 3 Absolute configuration Clockwise S Counterclockwise R Erythro and Threo Diastereomers Diastereomers are compounds with two or more chiral centers and are known to be stereoisomers that are not mirror images. ❑ If a diastereomer's Fischer projection has two identical substituents on the same side it is referred to be erythron. ❑ If a diastereomer's Fischer projection has two identical substituents on two opposite sides it is referred to be thero. i.e: 1) the product of the reaction of rans-crotonic acid with OsO4/H2O2 2) 2,3,4-trihydroxybutanal 3) Chloramphenicol 4) 3-chlorobutan-2-ol Meso compounds: ❑ A compound that exhibits reflectional symmetry will be achiral even though it has chirality centers. Such compounds are called meso compounds. ❑ A meso compound contains an internal plane of symmetry which makes it superimposable on its mirror image and is optically inactive although it contains two or more stereocenters. A meso compound must have 1. Two or more stereocenters. 2. An internal plane of symmetry. 3. The stereochemistry that cancels out, one of the two stereocenters should be R and the other S. i.e: 2,3-dichlorobutane These two stereoisomers are meso compounds because it has: ✓ Two chiral carbons ✓ Plane of symmetry ✓ One carbon is R and the other is S Conclusion: 2,3-dichlorobutane only has three possible stereosiomers, the pair of enantiomers and the meso compound. i.e: cyclohexane-1,2-diol This compound has two chirality centers and therefore we would expect 4 stereoisomers The second pair is just one compound, It has a plane of symmetry and is therefore a meso compound i.e: 1,3-dimethylcyclopentane Some other examples: Stereospecific and Stereoselective Syntheses ❑ Any reaction in which only one of a set of stereoisomers is formed exclusively or predominantly is called a stereoselective synthesis. The same term is used when a mixture of two or more stereoisomers is exclusively or predominantly formed at the expense of other stereoisomers ❑ In a stereospecific reaction, a given isomer leads to one product while another stereoisomer leads to the opposite product. ❑ All stereospecific reactions are necessarily stereoselective, but the converse is not true Stereospecificity of E2 Reactions on Substituted Cyclohexanes ❑ The E2 reaction proceeds via an antiperiplanar conformation. ❑ Substituted cyclohexane rings can adopt two different chair Conformations ❑ The E2 reaction only occurs from the chair conformation in which the leaving group is axial. ❑ The E2 reaction can only take place when the leaving group and the proton are on opposite sides of the ring (one on a wedge and the other on a dash). The addition of bromine to maleic and fumaric acids Maleic acid gives the dl pair of 2,3-dibromosuccinic acid, while fumaric acid gives the meso isomer. ▪ The reaction is stereospecific as well as stereoselective because two opposite isomers give two opposite isomers.