Stereochemistry MSC KCP Notes PDF

Organic Chemistry STEREOCHEMISTRY Dr. Ketan C Parmar DEPARTMENT OF CHEMISTRY Sir P. T. Sarvajanik College of Science, Surat INTRODUCTION: Stereochemistry deals with three dimensional representation of molecule in space. This has sweeping impli...

Organic Chemistry STEREOCHEMISTRY Dr. Ketan C Parmar DEPARTMENT OF CHEMISTRY Sir P. T. Sarvajanik College of Science, Surat INTRODUCTION: Stereochemistry deals with three dimensional representation of molecule in space. This has sweeping implications in biological systems. For example, most drugs are often composed of a single stereoisomer of a compound. Among stereoisomers one may have positive effects on the body and another stereoisomer may not or could even be toxic. An example of this is the drug thalidomide which was used during the 1950s to suppress the morning sickness. The drug unfortunately, was prescribed as a mixture of stereoisomers, and while one stereoisomer actively worked on controlling morning sickness, the other stereoisomer caused serious birth defects. The study of stereochemistry focuses on stereoisomers and spans the entire spectrum of organic, inorganic, biological, physical and especially supramolecular chemistry. Stereochemistry includes method for determining and describing these relationships; the effect on the physical or biological properties. STEREOCHEMISTRY: DEFINITION The branch of chemistry which deals with three dimensional structure of molecule and their effect on physical and chemical properties is known as stereochemistry. To represent molecule as three dimensional object we need at least one carbon sp3- hybridized. Example: H 2D drawing Not appropriate for steriochemistry Cl I Br H 3D drawing appropriate for steriochemistry Cl I Br  ISOMERISM The word isomerism originated from Greek word isomer (iso= equal; mers = part). When two or more organic compounds having similar molecular formula but exhibit differences in their chemical and/or physical properties are called isomers, and the phenomenon is known as isomerism. However, the stereochemistry of an organic compound can be defined as the chemistry of that compound in space and as a function of molecular geometry. Generally isomerism can be divided in to two categories; a. Structural (constitutional) Isomerism b. Stereo (configurational) Isomerism A. ISOMERS AND THEIR CLASSIFICATION You are already familiar with the concept of isomers: different compounds which have the same molecular formula. Here we will learn to make distinction between various kinds of isomers, especially the stereoisomers.  STRUCTURAL (CONSTITUTIONAL) ISOMERISM Structural isomerism is also known as ‘constitutional isomerism’. Structural isomerism arises when a molecule can be represented in to two or more than two different structures. The difference in structure is due to the difference in the arrangement of atoms within the molecules, irrespective of their position in space. In other words, structural isomers are compounds those have identical molecular formulae but different structural formulae; and the phenomenon is called structural isomerism. Structural isomerism can also be subdivided in to five types. 1) Chain Isomerism 2) Functional Isomerism 3) Position Isomerism 4) Metamerism 5) Tautomerism 1) Chain Isomerism: Chain isomers are those isomers having difference in the order in which the carbon atoms are bonded to each other. In other words chain isomers have variable amounts of branching along the hydrocarbon chain. If you observe two or more than two molecules having similar molecular formulae, but difference in their hydrocarbon chain length, you should recognize them as chain isomers of each other. 2) Functional Isomerism: Two or more than two molecules those having the same molecular formulae but have different functional groups are called functional isomers and the phenomenon is termed as functional isomerism. If you observe two or more than two molecules having same molecular formulae, but difference in their functional groups, you should understand that these are functional isomers of each other. Example 3: Ethyl alcohol and Dimethyl ether CH3CH2OH CH3OCH3 Ethyl alcohol Dimethyl ether Example 4: n-Butyl alcohol and Diethyl ether CH3CH2CH2CH2OH CH3CH2OCH2CH3 n-Butayl alcohol Diethyl ether 3) Position Isomerism: Two or more than two molecules those having same molecular formulae but having difference in the position of functional group on the carbon chain are called position isomers and the phenomenon is called as position isomerism. If you observe two or more than two molecules having same molecular formulae, but difference in their functional groups, you should understand that these are functional isomers of each other. Example 5: 1-Butene and 2-Butene CH3CH2CH CH2 CH3CH CHCH3 1-Butene 2-Butene Example 6:1-Butyl alcohol, 2-Butyl alcohol and t-Butyl alcohol CH3 CH3CH2CH2CH2OH CH3CHCH2CH3 CH3C OH OH CH3 1-Butyl alcohol 2-Butyl alcohol t-Butyl alcohol 4) Metamerism: Two or more than two molecules those having same molecular formulae and functional group but having difference in the distribution of carbon atoms on either side of functional group are called metamers and the phenomenon is called the metamerism. When you see two or more than two molecule with identical molecular formulae but while structural representation you observe there is a difference in the alkyl group attached to same functional group you should understand these molecules are metamers of each other. Example 7: Diethyl ether, Methylpropyl ether and isopropyl methyl ether CH3 CH3CH2OCH2CH3 CH3CH2CH2OCH3 CH3CHOCH3 Diethyl ether Methyl propyl ether Isopropyl methylether Example 8: Diethyl amine, Methylpropyl amine and isopropyl methyl amine CH3 CH3CH2NHCH2CH3 CH3CH2CH2NHCH3 CH3CHNHCH3 Diethyl amine Methyl propyl amine Isopropyl methylamine 5) Tautomerism: This is a special kind of isomerism where both the isomers are interconvertible and always exist in a dynamic equilibrium to each other. Due to their interconversion change in functional group takes place that gives two different isomers of an organic compound. This phenomenon is called Tautomerism. When you observe two different isomeric forms of an organic compound are rapidly interconvertible to each other you should recognize them as tautomer of each other. Remember: Tautomers are not the resonance structure of same compound Example 9: Acetone exists in taotomeric equilibrium with Prop-1-en-2-ol O OH CH3CCH3 CH3C CH2 Acetone Prop-1-ene-2-ol (keto form) (enol form) 1% Example 10: Tautomeric forms of Ethyl acetoacetate under taotomeric equilibrium O O OH O CH3CCH2COC2H5 CH3C CHCOC2H5 (keto form) (enol form) 93% 7%  STEREO (or CONFIGURATIONAL) ISOMERISM Stereoisomerism is arises due to the difference in arrangement (configuration) of atoms or groups in space. When two or more than two isomers have the same structural formulae but having difference in the arrangement (configuration) of atoms in space are called stereo isomer and the phenomenon is called stereo isomerism. Stereo isomerism can be further classified as i. Geometrical or cis-trans isomerism ii. Optical isomerism GEOMETRICAL ISOMERISM: Geometrical isomerism is generally observed in alkenes and cyclic compounds due to their restricted rotation around carbon- carbon bond. The rotation about a double bond in alkene or about a single bond in a cyclic/ring like compound is restricted. Double bonded system consists of a σ (sigma) and a π (pi) bond perpendicular to each other. It is not possible to rotate the molecule about carbon-carbon bond. The rotation will break the π bond as a result the molecule will lose its identity. In some cased the rotation about single bond is also restricted due to steric hindrance. Geometrical isomerism is shown by various groups of compounds the major class of compounds that exhibit geometrical isomerism are classified as: i. Compounds having double bond; C=C, C=N, N=N For example cis- and trans-2-butene have same connection of bond and molecular formulae. If you observe two similar groups are on the same side of C=C bond this is called cis- isomer; whereas, if two similar groups are on opposite side of C=C bond this is known as trans- isomer. Example 11: cis- and trans- isomerism in 2-butene H3C CH3 H3C H H H H CH3 cis-2-butene trans-2-butene You can understand that due to the presence of one σ (sigma) and one π (pi) bond in  carbon–carbon double bond, rotation around C=C bond is not possible. The restricted rotation around C=C bond is responsible for geometrical isomerism in alkenes. ii. Cyclic compounds like homocyclic, heterocyclic and fused-ring systems You can easily observe that rotation around C-C bond is also not possible in cyclic compounds as the rotation would break the bonds and break the ring. Thus Geometrical isomerism is also possible in cyclic compounds. Example 12: cis- and trans- isomers of 1,2-dimethylcyclopropane CH3 CH3 H H CH3 H H cis trans CH3 Conditions for geometrical isomerism: Following two conditions are necessary for any compounds to show geometrical isomerism a) There should be restricted (not allowed) rotation about a bond in a molecule. b) Both substituent/atoms on each carbon about which rotation is not allowed should (restricted) be different. Remember: Geometrical isomers are non-mirror image of each other hence they are called diastereomers. Therefore their physical and chemical properties are different. Triple bonded molecules do not exhibit any kind of stereoisomerism because such molecule shows cylindrical symmetry. E & Z system of nomenclature for geometrical isomers: We have already discussed about the cis- and trans- nomenclature of geometrical isomerism. The cis- and trans- nomenclature is the oldest and most fundamental nomenclature system for geometrical isomerism. The cis- and trans- nomenclature system is applicable only for those geometrical isomers in which at least one identical atoms/groups is bonded with each double bonded carbon. If both the identical groups/atoms are on same side of double bond the isomer is called as cis- isomer; whereas, if both identical groups/atoms are on opposite side of the double bond the isomer is called as trans- isomer (see example 1 of this unit). The cis- and trans- nomenclature method is limited to the molecule in which identical groups/atoms are attached to double bonded carbon. If all the atoms/groups on double bonded carbon are different then the configuration of such molecule could not be assigned as cis- and trans- nomenclature. A more general nomenclature (i.e. E/Z nomenclature) was introduced which was based on Cahn-Ingold-Prelog system. In E/Z system the configuration is specified by the relative positions of two highest priority groups/atoms on the two carbons of the double bond. Let us understand the E/Z nomenclature system by considering an example which we have already discussed in the beginning of this Unit (example 1). H3C CH3 H3C H C C C C H H H CH3 cis-2-butene trans-2-butene You can easily identify which one is cis- isomer and which one is trans- just by looking the position of similar atoms/groups. It is a simple and visual way of telling the two isomers apart. So why do we need an alternative system? Now consider one another example in which we will change all the atoms/groups in above example by replacing one CH3- by Br, other CH3- by Cl, and one H- by F. Now try to predict the nomenclature of these two isomers of 2-bromo-1-chloro-1-fluoroethene (I and II). Could you name these isomers using cis- and trans- nomenclature? The simplest answer is ‘NO’. Br Cl Br F C C C C H F H Cl I II Because all four atoms attached to the carbon-carbon double bond are different, therefore it is not so simple that you can predict them as cis- and trans- to each other. The E/Z system of nomenclature provides the most appropriate solution to above problem. This system is based on the priority of the attached atoms/groups on each double bonded carbon. The priority of the atoms/groups can be assigned as per the ‘Sequence Rule’ or ‘CIP Rule’ given by Cahn-Ingold- Prelog. We have discussed the detail about ‘Sequence Rule’ in later part of this Unit. Now assign priority to atoms/groups attached to each double bonded carbon in above example.  1 1 1 2 Br Cl Br F C C C C 2 2 2 1 H F H Cl Molecular Plane I II We can easily observe that the both higher priority atoms/groups on each double bonded carbon of isomer I are on same side; whereas, the higher priority atoms/groups on each double bonded carbon of isomer II are on opposite side. If the two groups with the higher priorities are on the same side of the double bond, such isomer is designated as the (Z)- isomer. So you would write it as (Z)-name of compound. The symbol Z comes from a German word ZUSAMMEN, which means together. If the two groups with the higher priorities are on opposite sides of the double bond, then such isomer is designated as (E)- isomer. E comes from the German ENTGEGEN, which means opposite. Thus in given example the isomer I is having both higher priority groups/atoms are on same side of double bond, hence it is Z- isomer; whereas, the isomer II is having both higher priority groups/atoms are on opposite side of the double bond, hence it is E- isomer. 1 1 1 2 Br Cl Br F C C C C Molecular Plane 2 1 2 I 2 II H F (Z)-2-bromo-1-chloro-1-fluoroethene H Cl (E)-2-bromo-1-chloro-1-fluoroethene Example 3 : Some other examples of geometrical isomers with E and Z configuration OPTICAL ACTIVITY We know that ordinary lights are composed of rays of different wavelengths vibrating in all directions perpendicular to the path of its propagation. These vibrations can be made to occur in a single plane by passing ordinary light through the polarizing Nicol prism. Such light whose vibrations occur in only one plane is called plane polarized light Compounds which rotate the plane of polarized light are called optically active compounds and this property is known as optical activity. Rotation of plane of polarized light can be of two types.  Dextrorotatory : If the compound rotates the plane of polarization to the right(clockwise) it is said to be dextrorotatory (Latin: dexter-right) and is denoted by (+), or ‘d’.  Laevorotatory : If the compound rotates the plane of polarization to the left(anticlockwise) it is said to be laevorotatory (Latin: laevus-left) and is denoted by (-) or ‘l’ The change in the angle of plane of polarization is known as optical rotation. The optical rotation is detected and measured by an instrument called polarimeter. The measurement of optical activity is reported in terms of specific rotation [α], which is given as, [α] λ t = α/lc [α]= specific rotation t = temperature of measurement λ=wavelength of the light used α= observed angle of rotation l= length of sample tube in decimeter c=concentration of the sample in g/mL of solution A. CHIRALITY  The term Chiral- The word chiral (Greek word Chier,meaning hand) is used for those objects which have right-handed and left-handed forms, i.e., molecules which have “handedness” and the general property of “handedness” is termed chirality. An object which is not superimposable upon its mirror image is chiral.  The term Achiral- Object and molecules which are superimposable on their mirror images is achiral. Achiral molecule has internal plane of symmetry, a hypothetical plane which bisects an object or molecule into mirror-reflactive halves. An object or molecule with an internal plane of symmetry is achiral.  The term Asymmetric center and chiral center- Three terms are used to designate, a carbon atom bonded tetrahedrally to four different substituents in a chiral molecule: Asymmetric atom, chiral center or stereocenter. A chiral centre * B D C Let us understand chiral and achiral center taking few more examples.  CH3 CH3 CH3 O * * H Cl H H H CH2CH2CH3 CH3 Br Br CH2CH3 H Chiral (asymmetric) Achiral Chiral Achiral has four different does not have has four different only has three atoms atoms bonded to four different groups bond to bonded to the carbon atoms bonded to the carbon carbon the carbon CHO CHO H * OH H * OH H * OH H * OH HO * H CH2OH CH2OH Chiral Chiral with two chiral centre with three chiral centre Chiral centres are shown by astrik (*)  The term stereogenic center or stereocenter- A stereogenic center is defined as an atom on which an interchange of any two atoms or groups result in a new stereoisomer, When the new stereoisomers is an enantiomer ,the stereocenter is called chiral center. All stereocenters are not tetrahedral. Example 1 COOH COOH Interchange between two groups H OH HO H (eg. H and OH) CH3 CH3 Steriocentre New Sterioisomer I II First and second are enantiomers (non superimposible mirror images), Hence the steriocentre is a chiral centre  Example- H3C CH3 H3C H Interchange between two groups C C C C on a sterio centre (eg. H and H H H CH3 CH3) Cis isomer New sterioisomer IV III III and IV are not enantiomers. they are diasteriomers hence in this case sterio centres are not chiral centres. Also these are not tetrahedral. Thus, all chiral centres are sterio centres but all steriocentres are not chiral centres. If a molecule contains only one chiral centres it must be chiral. Molecule containing two or more chiral centres may or may not be chiral. For example: meso tartaric acid has two chiral centres but it is achiral. COOH H OH H OH COOH Achiral due to presence of plane of symmetry B. STEREOISOMERS- Isomers having the same molecular formula but different spatial arrangement of their atoms are known as stereoisomer. They are of following types:  Enantiomers: Stereoisomers which are non superimposable mirror images of each other are called enantiomers. Chirality is necessary and sufficient condition for existence of enantiomers. These always exist as discrete pairs. Eg. COOH COOH HO H H OH CH3 CH3 Two isomers of Lactic acid   Diastereomers: Stereoisomers that are not mirror images of each other are called diastereomers. Example. Mirror Mirror CH3 CH3 CH3 CH3 H OH HO H H OH HO H Br H r H B H Br Br H CH3 CH3 CH3 CH3 OPTICAL ACTIVITY (ENANTIOMERISM): It is already known to you (from section 4.5) that the optical activity is an ability of a chiral molecule to rotate the plane of plane-polarized light either towards left or right direction. The rotation is measured by an instrument called Polarimeter. When a beam of plane polarized light passes through a sample that can rotate the plane polarized light, the light appears to dim because it no longer passes straight through the polarizing filters. The amount of rotation is quantified as the number of degrees that the analyzing lens must be rotated to observe the no dimming of light appears. Optical rotation can be measured by using the following formulae Where α is observed angle of rotation; t is the temperature of during experiment; λ is the wavelength of light used; l is the length of the tube in decimeter; and c is the concentration of the compounds per 100 mL of solution. Optically active chiral compounds that are non-super imposable mirror image of each other arecalled enantiomers.  Properties of enantiomers: The main properties of enantiomers are given as follow o Enantiomers always exist in pair o Enantiomers are non-super imposable mirror image to each other o Enantiomers have same physical properties (like boiling point, melting point, solubility, density, viscosity, refractive index etc.)and chemical properties in achiral environment Each enantiomers have opposite behavior with respect to plane polarized light, if one of them will rotate the plane polarized light towards right hand direction then definitely theother will rotate the plane polarized light towards left hand direction. o Each enantiomers shows the same chemical reactivity with achiral reagent; howeverthey have different reactivity with chiral reagent. DIASTEREOMERS: Diastereomers are those stereoisomers that are not mirror image of each other, in other words you can understand the diastereomers are stereoisomers that are not enantiomers. Diastereomers are non- enantiomeric stereoisomers with two or more stereo centers. The pair of stereoisomer that differs in the arrangement of atoms/groups bonded with at least one stereo centre is called diastereomers. PROPERTIES OF DIASTEREOMERS: The main properties of diastereomers are given as follows:  All the stereoisomers except enantiomers are diastereomers.  Diastereomers have different physical properties like boiling point, melting point,density, solubility, density, viscosity, refractive index etc.  Diastereomers have different chemical properties like rates of reactions, reactivityeven in achiral reaction medium.  This difference in physical and chemical properties of diastereomers is veryuseful in the separation of enantiomers from their mixture.   Geomatrical Isomers: Geometrical isomers occurs as a result of restricted rotation about a carbon-carbon bond. This is also called cis-trans isomerism. This isomerism exhibited by variety of compounds such as compound containing double bond C=C, C=N, N=N, compound containing cyclic structure or compound containing restricted rotation due to steric hindrance.  Conformational isomers: Conformational isomers are the isomers that can be converted into one another by rotation around a single bond. Example: eclipsed, gauche and anti butane are all conformational isomers of one another.(eclipsed means that identical groups are all directly in line with one another, gauche means that identical groups are 60 degree from one another and anti means that identical groups are 180 degree from one another.) CH3 CH3 CH3 CH3 H H H CH3 H H H H H H H H CH3 H Eclipsed Anti Gauche These molecules can be interconverted by rotating around the central carbon-carbon single bond. REPRESENTATION OF THREE DIMENSIONAL MOLECULES FLYING-WEDGE OR WEDGE-DASH PROJECTION The Flying-Wedge Projection is the most widely used three dimensional representation of a molecule on a two dimensional surface (paper). This kind of representation is usually done for molecule containing chiral centre. In this type of representation three types of lines are used.   A solid wedge or thick line ( ) - it represents bond projection towards the observer or above the plane of paper.  A continuous line or ordinary line ( ) - it represents bond in the plane of paper.  A dashed wedge or broken line ( ) - it represents bond projection away from the observer or below the plane of paper. Example:- CH4 (methane) H H H H “Ball and stick” model sketched 3-D structural of 3-D structure of methane formula of methane FISCHER PROJECTION Fischer projection provide an easy way to draw three dimensional molecule on two dimensional paper and all the bonds are drawn as solid lines around asymmetric carbon atom. The Fischer rules for showing the arrangement around asymmetric carbon.  The carbon chain of the compound is projected vertically, with the most oxidized carbon at the top or place the carbon number one at the top (as defined by nomenclature rule).  The chiral carbon atom lies in the plane of the paper and usually omitted. The intersection of cross lines represents asymmetric carbon.  The horizontal bonds attached to the chiral carbon are considered to be above the plane of paper or point towards the observer.  The vertical bonds attached to the chiral carbon are considered to be below the plane of paper or point away from the observer.  Example: glyceraldehyde CHO CHO H OH H OH CH2OH CH2OH SAWHORSE FORMULA The sawhorse formula indicates the arrangement of all the atoms or groups on two adjacent carbon atoms. The bonds between the two carbon atoms are drawn diagonally and of relatively greater length for the sake of clarity. The lower left hand carbon is taken as the front carbon or towards the observer and the upper right hand carbon as the back carbon or away from the observer. e.g. ethane Anti conformation eclipsed conformation  All parallel bonds in sawhorse formula are eclipsed and all anti parallel bonds are opposite or scattered. Gauche representation is that in which bulky groups are nearer to each other at 600 angles. NEWMAN PROJECTION Newman devised a very simple method of projecting three dimensional formulas ontwo dimensional paper which are known as Newman projection.  In these formulae the molecule is viewed from the front or along the axis of a carbon-carbonbond.  The carbon nearer to the eye is represented by a point and the carbon atom towards the rearby circle.  The three atoms or groups on the carbon atoms are shown as being bonded to dot or circle byan angle of 1200 to each other.  In Newman formula all parallel bonds are eclipsed or all anti parallel or opposite bonds arestaggered. Eclipsed Anti Gauche ELEMENTS OF SYMMETRY Elements of symmetry are a simple tool to identify whether a molecule is chiral or not. The necessary condition for optically active molecule to be chiral is that, the molecule should not possess any kind of symmetry elements. The elements of symmetry are generally categorized as follows: (i) Simple axis of symmetry (Cn) (ii) Plane of symmetry (σ) (iii) Centre of symmetry (Ci) (iv) Alternating axis of symmetry (Sn)  (i) Simple axis of symmetry (Cn): When a rotation of 360°/n (where n is any integer like 1,2,3…etc.) around the axis of a molecule or object is applied, and the rotated form thus obtained is non-differentiable from the original, then the molecule/object is known to have a simple axis of symmetry. It is represented by Cn. Example 13: Water molecule has C2 (two fold axis of symmetry) whereas chloroform has C3 axis of symmetry. From above example you can easily understand that if you rotate the water molecule by 180° (i.e. 360°/2=180°) along its molecular axis you will get the identical (non- differentiable) form of water molecule, hence water molecule has two fold of symmetry. Similarly, if you rotate the chloroform molecule by 120° (i.e. 360°/3=120°) along its molecular axis you will get the identical (non-differentiable) form of chloroform molecule, hence chloroform molecule has three fold of symmetry. (ii)Plane of symmetry (σ): It is defined as ‘when a plane that devised a molecule or object in to two equal halves which are related to object and mirror image is known as plane of symmetry. It is represented by σ. Example 14: Plane of symmetry in Tartaric acid Palne that devides d molecule in two equal halves COOH a C b H C OH a C b H C OH d COOH Sybmbolic representation 2,3-dihydroxysuccinic acid (Tartaric acid)  From above example you can easily understand that if we put a mirror plane/reflection plane exactly at the centre axis of the molecule/object; you will found that the mirror image thus obtained is the complementary of the original and both will give us the appearance of complete molecule/object. A molecule has a centre of symmetry when, for any atom in the molecule, an identical atomexists diametrically (diagonally) opposite to this centre and at equal distance from it. Example 15: An isomer of 1,3-dichloro-2,4-dibromocyclobutane has a centre of symmetry From above example you may understand that all the identical atoms are situateddiagonally and at equal distance from the centre. This is called centre of symmetry. (ii) Alternating axis of symmetry (Sn): An alternate axis of symmetry is defined as, when a molecule is rotated by 360°/n degrees about its axis and then a reflection plane is placed exactly at perpendicular to the axis, and the reflection of the molecule thus obtained is identical to the original. It is represented by Sn. Example 16.An isomer of 1,3-dichloro-2,4-dibromocyclobutane has a 2 fold alternate axis ofsymmetry NOMENCLATURE OF OPTICAL ISOMERS Following three nomenclatures are used for optically active compounds: D, L SYSTEM OF NOMENCLATURE This nomenclature is mainly used in sugar chemistry or optically active polyhydric carbonyl compounds. This is a relative nomenclature because all the configurations described with respect to glyceraldehydes. All sugars whose Fischer projection formula shows the OH group on the right hand side of the chiral atom belong to the D-series. CH3 H C OH CH2OH D-series.  Similarly, if OH is on the left hand side, then the sugar belongs to the L-series. CH3 HO C H CH2OH L-series  It must be noted that there is no relation between sign of rotation and (+, - or d,l ) and configuration (D and L) of enentiomer.  Any compound that can be prepared from, or converted in to D(+) glyceraldehydes will belong to D-series and similarly any compound that can be prepared from, or converted in to L(-) glyceraldehydes will belongs to the L-series. ERYTHRO AND THREO SYSTEM OF NOMENCLATURE This nomenclature is mainly used only in those compounds which have only two chiral carbons and the following structures: R’-Cab-Cab-R’’ or R’-Cab-Cbc-R’’ i.e. out of six substituent on two asymmetric carbons, at least one should be same in both the carbons. When two like groups in fisher projection formula are drawn on the same side of vertical line, the isomer is called erythro form; if these are placed on the opposite sides the isomer is said to be threo form. Following are some examples of threo and erythro form. R.S. NOMENCLATURE The order of rearrangement of four groups around a chiral carbon is called the absolute configuration around that atom. System which indicates absolute configuration was given by three chemists R.S. Cahn, C.K. Ingold and V. Prelog. This system is known as (R) and (S) system or the Cahn-Ingold Prelog system. The letter (R) comes from the Latin rectus (means right) while (S) comes from the Latin sinister (means left). Any Chiral carbon atoms have either an (R) configuration or a (S) configuration. Therefore one enantiomer is (R) and the other is (S). A recemic mixture may be designated as (RS), meaning a mixture of the two. The R, S nomenclature involves two steps: Step I: The four ligands (atom or groups) attached to the chiral centre are assigned a sequence of priority according to sequence rules.  Rule 1: If all the four atoms directly attached to the chiral carbon are different, priority depends on their atomic number. The atom having highest atomic number gets the highest priority, i.e., (1).The atom with lowest atomic number is given lowest priority, i.e. (2), the group with next higher atomic number is given the next higher priority (3) and so on. For example: Rule 2: if two or more than two isotopes of the same element are present, the isotope of higher mass receives the higher priority. Rule 3: if two or more of the atoms directly bonded to the chiral carbon are identical, the atomic number of the next atom is used for priority assignment. If these atoms also have identical atoms attached to them, priority is determined at the first point of difference along the chain. The atom that has attached to it an atom of higher priority gets the higher priority.  In the above example, the atoms connected directly to the chiral carbon are iodine and three carbons.  Iodine has the highest priority.  Connectivity of other three carbons are 2H and Br, 2H and C and 2H and C.  Bromine has the highest atomic number amongst C, H, Br and thus CH2Br has highest priority among these three groups (i.e. priority number 2).  The remaining two carbon are still identical (C and 2H) connected to the second carbon of these groups are 2H and I and 2H and C. Iodine has highest priority.  Amongst these atoms, so that-CH2-CH2-I is next in priority list and CH2-CH2-CH3 has the last priority. Rule 4: If a double or a triple bond is linked to chiral centre, the involved electrons are duplicated or triplicated respectively. STEP-II: The molecule is then visualised so that the group of lowest priority (4) is directed away from the observer (at this position the lowest priority is at the bottom of the plane). The remaining three groups are in a plane facing the observer. If the eye travels clockwise as we look from the group of highest priority to the group of second and third priority (i.e. 1 2 3 with respect to 4) the configuration is designated R. If arrangement of groups is in anticlockwise direction, the configuration is designated as S. For example: In this Fischer projection, the least priority number is not at the bottom of the plane. In such cases, the Fisher projection formula of the compound is converted in to another equivalent projection formula in such a manner that atom the lowest priority is placed vertically downward. This may be drawn by two interchanges between four priority numbers. The first interchange involves the two priority numbers, one is the least priority number and the other is the priority number which is present at the bottom of the plane. In the above case, first interchanges will takes place between 2 and 4. An alternative, simple and most widely accepted procedure used now (Epling,1982) to assign R,S configuration in the case of Fischer projections is as followes: Case-I: R and S nomenclature from Fischer projection formula (Golden rule): If in a Fischer projection, the group of lowest priority (4) is on a vertical line, then the assignment of configuration is R for a clockwise sequence of 1 to 2to 3 and S for anticlockwise sequence. For example: F 4 Br I 2 1 2 1 Cl 3 3 Anticlockwise arrangement hence S- configuration However, if the group of lowest priority is on horizontal line, then the assignment of configuration is S for a clockwise sequence of 1 to 2 to 3, and R for the anticlockwise sequence. CHO 2 2 H OH 4 1 1 CH2OH 3 3 Anticlockwise arrangement but lowest priority at horizontal line hence R- configuration When molecule contain two or more chiral centres, each chiral centre is assigned an R or S configuration according to the sequence and conversion rules. Thus (+) tartaric acid is (2R, 3R) (+) tartaric acid. COOH 2 H OH HO 3 H COOH Configuration at chiral carbon - 2. COOH 2 2 H OH 4 1 1 CHOHCOOH 3 3 Configuration at chiral carbon - 3. RACEMIC MIXTURE (RACEMATES) A Racemic mixture is an equimolar mixture of a pair of enantiomers. The racemic mixture or racemates are optically inactive due to mutual or external compensation of two enantiomeric constituents. Racemic mixture in liquid and vapor phase shows physical properties (like boiling points, density, refractive index etc.) identical to those of pure enantiomers. However, the solid phase enantiomeric mixtures have some properties different from the pure enantiomers. i. Remember: Racemic mixture is not a meso compound; since both are optically inactive. The racemic mixture is an equimolar mixture of two enantiomers whereas meso is asingle compound. Meso compounds are optically inactive because of the internal compensation; however, the racemic mixtures (racemates) are optically inactive because of the external compensation. You might have aware with that the enantiomerically pure compounds are of great importance in chemical and pharmaceutical areas. But during the synthesis of optically active compounds using achiral reaction condition and achiral reagents, it always gives racemic mixture (racemates). Therefore to obtain the pure enantiomers we must have to separate the racemic mixture in to corresponding pure enantiomers. Thus, the separation process of a racemic mixture in to its pure individual enantiomeric constituents is called resolution of racemic mixtures (resolution of enantiomers).Since enantiomers have identical physical properties(like solubility, boiling point, melting point, density, refractive index etc.),therefore, they cannot be separated by common physical techniques such as direct crystallization, distillation or basic chromatography. There are four general methods that are extensively being used for the resolution of racemic mixtures. i. Mechanical separation (crystallization method) method ii. Diastereomer formation method iii. Chromatographic method iv. Biochemical/enzymatic methods STEREOCHEMISTRY OF ALLENES, SPIRANES; BIPHENYLS, In above sections of this unit we have discussed about the compounds containing one or more stereocentres and their chirality is specified at these centres. However, there are a class of compounds with nonsuperimposable mirror images it is not possible to identify a stereocentre, then to predict the stereochemistry of such compounds it becomes necessary to focus our attention on other aspects of the molecule. Thus, the presence of stereocentre is not a necessary and sufficient condition for molecular dissymmetry. The overall chirality of a molecule can be categorised in to three elements; i) stereocentres; ii) stereoaxes; and iii) stereoplanes, one other element of chirality is still there and called helicity. Chirality due to axes (Axial chirality): Such type of chirality is produced in a molecule when there is no chiral centre present in the molecule. As discussed, in order to produce chirality it is not necessary for all of the substituents to be different. However, it is sufficient to have each substituent different from its nearest neighbour. When four atoms/groups attached to a central atom are located on the corners of tetrahedron the central atom is termed as chiral centre. If the chiral centre is replaced by a linear grouping like C- C or C=C=C, the tetrahedron geometry get extended along the axis of the grouping and thus generates a chiral axis. Depending on the nature of groups attached with the carbon atoms, some examples of molecules with chiral axis are allenes, biphenyls, alkylidenecycloalkanes, spiranes, adamentanes etc.; are shown below (Figure). a d a a d a d a a a C C C c b b c b b c b bb Allene Biphenyl alkylidenecycloalkane Spirane Adamantane Figure: examples of molecules with chiral axis are allenes, biphenyls, alkylidenecycloalkanes, spiranes and adamentane Allenes: Allenes are compounds with two or more double bonds side-by-side. Such bonds are called cumulated double bonds. The central carbon of allene forms two sigma bonds and two pi bonds. The central carbon is sp-hybridized and the two terminal carbons are sp2-hybridized. The two π-bonds attached to the central carbon are perpendicular to each other. The geometry of the π-bonds causes the groups attached to the end carbon atoms to lie in perpendicular planes (Figure). The bond angle formed by the three carbons is 180°, indicating linear geometry for the carbons of allene. Figure : Planar depiction of allene molecule Stereochemistry of Allenes: When three or more adjacent carbon atoms in a molecule are bonded by double bonds, the compounds is called cumulene or said to have cumulative double bonds. Allene is the simplest example of this class. Allenes are chiral and they have nonsuperimposable mirror images and exist as enantiomers although they have no chiral centre. Stereochemistry of Alkylidenecycloalkanes: The replacement of double bonds in allene by a cycloalkane ring gives the alkylidenecycloalkane; such replacement does not change the basic geometry of the molecule. The suitably substituted alkylidenecycloalkanes also exhibit enantiomerism. The enantiomerism in such compounds is also due to the presence of chiral axis. For example, 4-methylcyclohexyldene acetic acid has been resolved into two enantiomers. Stereochemistry of Spiranes: When both the double bonds in allenes are replaced with the ring system the resulting compounds are known as spiranes or spiro compounds. The conditions for chirality in spiranes are similar to those of allenes. The two rings of spiranes are perpendicular to each other; therefore, proper substitution on the terminal carbon will make the molecule chiral and thus exhibit enantiomerism. The chirality in the spiranes is also due to the presence of chiral axis. For example, Diaminospiroheptane can be resolved in to its enantiomers. Stereochemistry of Biphenyls: Stereoisomers obtained due to the restricted rotation about carbon-carbon single bond are called atropisomers and the phenomenon is called atropisomerism. Such compounds also have the chirality due to the axis. Suitably substituted biphenyls exhibit enantiomerism due to the presence of chiral axis. This enantiomerism arises due to atropisomerism i.e. restricted rotation around C-C bond between two phenyl rings. This steric hindrance of substituents at ortho- position of the each ring is responsible for such restricted rotation. To maintain the maximum stability, molecule orients itself in such a manner so that both the ortho- substituted phenyl rings lie in different plane. Biphenyl shows the enantiomerism when the molecule has the following properties. a) Each ring must be unsymmetrically substituted. Each of the rings should not contain any kind of symmetry element. a a a b a b b b b a b ab b b I II III nonresolvable Biphenyl resolvable Biphenyls (optically inactive due to plane of (optically active due to absence symmetry) of symmetry elements) b) Suitable substitution (at least one substitution) at ortho- position must be there at each rings. c) othro- substituents must be larger in size (-Cl, -Br, -I, -COOH, -NO2, -NHCOCH3, - SO3H, -R groups etc.). The smaller groups at othro- position make the compounds planar in nature and thus do not exhibit atropisomerism. Chirality due to Plane (Planar Chirality): Chirality shown by a molecule due to the asymmetry in molecular plane is called chirality due to plane. The chirality is particularly due to the out of the plane arrangement of atoms or groups in the molecule with respect to reference plane, hence called chiral plane. The most important example of the molecule with chiral plane is cyclophanes. Other examples are trans-cyclooctene, bridged annulenes and metallocenes etc. CH2 n CH2 CH2 O O COOH HOOC Br Polymethylene ether of hydroquinone paracyclophane paracyclophane (S)- (R)- trans-cyclooctene The polymethylene bridge is perpendicular to the plane of the benzene ring; the substituent Br restricts the rotation of the benzene nucleus inside the methyl bridge, that makes the molecule chiral. Similarly the simple paracyclophane can be resolved because the benzene ring cannot rotate in such a way that the carboxylic passes through the acyclic ring. The plane of both the aromatic rings is approximately parallel to each other. Similarly the trans-cyclooctene also exhibits the chirality due to the presence of chiral plane.  TOPOCITY Stereo-chemical relationships between individual atoms or groups within a single molecule can be defined in terms of topicity. Thus, two atoms equated by a mirror reflection of the molecule are enantiotopic and two atoms in equivalent environments (i.e., the methylene protons in n- propane) are homotopic. Two protons placed in diastereomeric positions by a mirror reflection are in diastereotopic environments. Examples 17: Propane has homotopic ligands; however, propionic acid has enantiotopic ligands O O O simultaneous replacement H 3C of Ha and Hb by OH H3C H 3C OH OH OH Ha Hb Ha OH HO Hb Propionic acid Both the compounds are enantiomer (prochiral molecule Ha and Hb are enantiotopic) simultaneous replacement HO Hb Ha Hb of Ha and Hb by OH Ha OH H3C CH3 H3C CH3 H3C CH3 Propane Ha and Hb Both the compounds are identical are homotopic  PROCHIRAL CENTER AND PROCHIRAL MOLECULE: As we discussed in Unit 4 (Stereochemistry I) of this module; a tetrahedrally bonded atom with four different atoms or groups (Cabcd) is called a chiral molecule. However, a tetrahedrally bonded atom with two identical atoms or groups (Cabbc) is called an achiral molecule. If replacement of one of the identical groups in an achiral molecule of type Cabbc with a different group when gives an asymmetric molecule then the achiral center is called prochiral center and the molecule is called prochiral molecule. This property is called prochirality. Example 18: Propionic acid is a prochiral molecule with centre carbon atom as prochiral centre. Replacement of one of the hydrogen atom by a different group gives the optically active compound. O O O C2 H5 simultaneousreplacement C2 H 5 of Ha and Hb by Cl C 2H 5 OH OH OH Ha Hb Ha Cl Cl Hb Butanoic acid Both the compounds are enantiomer (prochiral molecule Ha and Hb are enantiotopic) HOMOMORPHIC LIGANDS: Two apparently identical atoms/groups of a prochiral centre are called homomorphic atoms/groups. These are also known as homomorphic ligands. Homomorphic is a Greek name where homos meaning similar and morphe meaning form. Thus two homomorphic ligands are indistinguishable during their isolation. Two hydrogen atoms of Propionic acid are apparently identical groups i.e. H atoms of methylene group are called homomorphic atoms or ligands. STEREOHETEROTOPIC LIGANDS: Consider two molecules, Butanoic acid in which two identical hydrogen atoms attached with methylene carbon, and 2-butanol in which two identical hydrogen atoms of methylene carbon. Replacement of any one of the homomorphic ligands in butanoic acid will give a pair of enantiomer; however, replacement of any one of the homomorphic ligands in 2-butanol will give the formation of two diastereomers. Since enantiomers and diastereomers are stereoisomers therefore the homomorphic groups or ligands are also called stereoheterotopic groups or ligands. Example 19: Stereoheterotopic ligands (Ha and Hb) of butanoic acid and 2-butanol. Simultaneous replacement of Ha and Hb in both the compounds leads the formation stereoisomers.  PROCHIRALITY: It is the property of some molecules due to which these molecules can be converted in to stereoisomers (enantiomers or diastereomers) by replacing one of the identical atoms or groups by a different atom or group. It is also known as ‘prostereoisomerism’ more specifically. If the replacement of such atoms or groups leads the formation of enantiomer the atoms or groups are called enantiotopic; whereas, if such replacement lead the formation of diastereomers the atoms or groups are termed as diastereotopic. HOMOTOPIC LIGANDS AND FACES: When replacement of two H atom in a methylene carbon of a molecule generates two identical compounds instead of stereoisomers, these two hydrogen atoms are called homotopic ligands. Example 20: Let us consider the case of formaldehyde, the two hydrogen atoms of formaldehyde when replaced with a different atom or group generates two identical compounds hence both the hydrogen atom of formaldehyde molecules are homotopic atoms or homotopic groups. O O O simultaneous replacement of Ha and Hb by Cl Cl Hb Ha Hb Ha Cl Identical Example 21: Similarly there is no way to differentiate between the two faces of formaldehyde molecule. The addition of Grignard reagent RMgX to either faces gives the identical compound ethanol. Hence, two faces of formaldehyde are also homotopic faces. O HO OH Ha Ha RMgX R Hb Hb R Ha Hb dry ether Identical Substitution/addition and symmetry are the two key criteria to determine the topicity of homomorphic ligands and faces. Two homomorphic ligands are called homotopic if replacement of each one of them by another atom or group leads to the identical structure. Thus we can consider three hydrogen atom of acetic acid as homotopic hydrogen, similarly three hydrogen of toluene are also called homotopic hydrogen, because replacement of each one of them will lead the same structure. Example 2 2 : In (2R,3R)-2,3-dihydroxytartaric acid two homotopic hydrogen atoms are present;replacement of each one of them by a different atom gives identical compounds. Identical COOH COOH COOH 1 simultaneous replacement 1 1 H C OH of Ha and Hb by Cl Cl C OH H C OH HO C H HO C H 2 HO C Cl 2 2 COOH COOH COOH (2R,3R) 2,3-Dihydroxytartaric acid (2S)-2-chloro-2,3-dihydroxysuccinic acid Example 23: In a double bonded compound like cis-2-butene, two faces of double bond are homotopic since addition on either faces gives the same product. The epoxidation of double bond on either face gives meso product [(2R,3S)-2,3-dimethyloxirane]. Homotopic ligands and faces can also be determined by employing symmetry operations on the molecule. Let us consider an example of acetic acid, in which all three hydrogen atom of methyl group are homotopic. Two successive rotation of methyl group around its C3 axis (with the rotation angle of 120°) allow each hydrogen atom to occupy the position of either of the other two hydrogen atoms without effecting any structural changes. As we know that hydrogen atom of methyl group interchanges their position rapidly in 3 dimensional planes, due to this rapid interchange of hydrogen atoms of methyl group leads the formation of indistinguishable structure, that’s why these hydrogen atoms are called homotopic hydrogen (homotopic ligands). Similarly, both the faces of cis-2-butene, formaldehyde and symmetrical ketones are homotopic, hence called homotopic faces. Remember: A molecule contains two equivalent atoms/groups they would not be homotopic if the other two groups are different. Such molecules are known as prochiral molecule.  ENANTIOTOPIC LIGANDS AND FACES: When the replacement of each equivalent atom or groups by a different atom given enantiomeric products, such equivalent atoms or groups are called enantiotopic atoms or enantiotopic ligands. Example 24: For example, two hydrogen atoms of meso-tartaric acid are enantiotopic since thereplacement of each one of them by a different atom or group gives the enantiomeric pair of(2S)-2-chloro-2,3-dihydroxysuccinic acid and (2R)-2-chloro-2,3-dihydroxysuccinic acid. Enantiomer COOH COOH COOH 1 simultaneous replacement H C OH hydrogen by Cl Cl C OH H C OH H C OH HO C H Cl C OH 2 COOH COOH COOH (2S)-2-chloro-2,3- (2R)-2-chloro-2,3- 2,3-dihydroxysuccinic acid dihydroxysuccinic acid dihydroxysuccinic acid (meso) Similarly, when two faces of a double bond gives enantiomers on addition of suitable reagents, such faces are called enantiotopic faces. For example, trans-2-butene and unsymmetrical ketones have enantiotopic faces since they also give enantiomers on addition of suitable reagents. Example 25: Epoxidation of trans-2-butene on either face of double bonds gives the enantiomericpair of (2R,3R)-2,3-dimethyloxirane and (2S,3S)-2,3-dimethyloxirane. H CH3 Epoxidation O H CH3 C C H3C H H C C CH3 + C C H3C H OOH H3C H O Cl trans-2-butene O (2R,3R)-2,3-dimethyloxirane (2S,3S)-2,3-dimethyloxirane Example 10: Similarly, addition of the Grignard reagent (RMgX; R=C2H5) or other organometallic reagents on either faces of unsymmetrical carbonyl compounds gives enantiomers. Hence, faces ‘a’ and ‘b’ of acetaldehyde (1) and Pentan-2-one (2) are called enantiotopic faces. Unlike homotopic ligands and faces, enantiotopic ligands and faces cannot be interchanged by a simple axis of symmetry (Cn). However, they can be interchanged by plane of symmetry, center of symmetry (i) and alternative axis of symmetry (Sn). NOMENCLATURE OF ENANTIOTOPIC LIGANDS AND FACES: Naming of enantiotopic ligands and faces is based on the CIP sequence rule by arbitrarily assigning priority to the homomorphic groups/ligands/faces. Example 26: Let us consider ethanol with two homomorphic ligands (Ha and Hb). If Ha is arbitrarily preferred over Hb in the sequence rule, the priority order of the attached groups at central carbon will be OH>CH3> Ha> Hb and the hypothetical configuration of the stereocenter will be R, thus Ha is designated as pro-R and Hb is designated as pro-S. Similarly, if Hb was arbitrarily given higher priority over Ha in that case according to sequence rule priority order would have been OH>CH3> Hb> Ha and the hypothetical configuration of ethanol would be S, thus Hb is designated as pro-S and Ha is designated as pro-R. Replacement of Ha by deuterium ‘D’ gives (R)-ethanol-1-D, hence, Ha is pro-R; similarly, replacement of Hb by D gives (S)- ethanol-1-D, hence, Hb is pro-S. Similalry, two faces of carbonyl carbon are termed as enantiotopic faces. These faces can be designated as Re-Si nomenclature. The groups around the carbonyl group are given priorities as per CIP sequence rule for R and S nomenclature. While going from the highest priority group to the lowest priority group around the faces of carbonyl group, if the path followed is clockwise the faces is Re and if it is anticlockwise, the face is Si. 1 1 O O 2 2 3 3 Si-face Re-face DIASTEREOTOPIC LIGANDS AND FACES: When the replacement of either of two homomorphic ligands or atoms of a molecule by a different atom generates diastereomers, such homomorphic ligands or atoms are called diastereotopic ligands or atoms. Example 27: Let us consider an example of propene in which two homomorphic hydrogen are present. Replacement of one of the homomorphic hydrogen with a hetero atom Cl gives Z-alkene ((Z)-1-chloroprop-1-ene) while replacement of other homomorphic hydrogen atom by Cl generates E-alkene ((E)-1-chloroprop-1-ene). Both, (Z)-1-chloroprop-1-ene and (E)-1- chloroprop-1-ene are stereoisomer but non mirror image of each other, hence are called diastereomer. Thus, two hydrogen atoms (i.e. Ha and Hb) of 1-propene are diastereotopic.  H Cl C C H3 C H H Ha simultaneous of H and Hreplacement by Cl (E)-1-chloroprop-1-ene C C a b H3C Hb H H 1-propene C C H3 C Cl (Z)-1-chloroprop-1-ene Example 28: Consider another interesting example of R-2-butanol with a stereocenter at C1 and two homomorphic hydrogen atoms (Ha and Hb) at C2. Replacement of Ha leads to the formation of (2R,3R)-3-chlorobutan-2-ol, and replacement of Hb leads the formation of (2R,3S)-3- chlorobutan-2-ol. Therefore, these two products are diastereomers, and the two protons (Ha and Hb) of R-2-butanol are diastereotopic. HO H H3 C CH3 Cl H HO H simultaneous replacement H3C of Ha and Hb by Cl (2R,3R)-3-chlorobutan-2-ol CH3 Ha Hb HO H H3C R-2-butanol CH3 H Cl (2R,3S)-3-chlorobutan-2-ol The two faces of carbonyl group next to a stereocenter are diastereotopic. Since, addition of reagents (like HCN, RMgX, HCl etc.) from either faces gives diastereomers. Thus, two faces of such carbonyl group are termed as diastereotopic faces. Example 29: For example, let us consider addition of HCN to the either faces of carbonyl group of (S)-3-phenylbutan-2-one leads to the formation of, (2S,3S)-2-hydroxy-2-methyl-3- phenylbutanenitrile and (2R,3S)-2-hydroxy-2-methyl-3-phenylbutanenitrile, a pair of diastereomers. C 6 H5 CH3 a C6H5 C 6 H5 CH3 addition of HCN from CH3 CN CN H O + HCN face 'a' and face 'b' H + H OH OH H3C H 3C b H3C (S)-3-phenylbutan-2-one (2S,3S)-2-hydroxy-2-methyl- (2R,3S)-2-hydroxy-2-methyl- 3-phenylbutanenitrile 3-phenylbutanenitrile Example 30: Similarly, consider another example of 4-t-butylcyclohexanone in which addition of hydride on either faces of carbonyl group leads the formation of trans- and cis- 4-t- butylcyclohexanol (diastereomers). Thus two faces of 4-t-butylcyclohexanone are diastereotopic faces. H a H3C H- H3C OH O H3C trans- 4-tert-butylcyclohexanol (diequatorial) H3C addition of hydride on OH H3C either faces CH3 H3C b H 4-tert-butylcyclohexanone H3C H3C cis-4-tert-butylcyclohexanol The addition of hydride on either faces of 4-t-butylcyclohexanone gives two diastereomers (achiral) products. Hence, the carbonyl carbon is considered as prostereo center rather than prochiral center. ASYMMETRIC INDUCTION Before 1940, the optically active compounds could be obtained in stereoisomerically pure form only by isolation of racemic mixture of optically active compounds from natural products and their subsequent enzymatic resolution. Since, equimolar amount of enantiomers (racemic mixture) is obtained when a prochiral molecule undergoes reaction in the absence of chiral environment. As we know the physical and chemical properties of enantiomers are always same in the absence of a chiral environment. However, enantiomers have entirely different reactivities in biological system. Asymmetric induction is a stereo chemical transformation (reaction) that results the preferential formation of one enantiomer or diastereomer over other in the presence of a chiral substrate, reagent, catalyst or environment. This is also known as asymmetric synthesis. The chiral agent must play an active part in the asymmetric induction. Such chiral agent has an important role in the formation of transition state. The direct synthesis of an optically active substance from optically inactive compound with or without the use of any optically active compound is called asymmetric synthesis. In general asymmetric synthesis can also be defined as the synthesis which converts a prochiral unit in to a chiral unit and formation of unequal amount of stereoisomers. PRINCIPLE OF ASYMMETRIC SYNTHESIS: There are three principle of asymmetric synthesis a) The substrate molecule must be prochiral i.e. the substrate must have either enantiotopic or diastereotopic ligands or faces. b) There must be presence of chirality in the reaction/asymmetric transformation for the preferential formation of one stereoisomer over the other. Either the substrate, or the reagent, or the solvent, or the catalyst must be enantiomerically pure. c) The chiral agent must play an important role in the reaction and must involve in the formation of two diastereomeric transition states. Example 31: Let us consider hydrogenation of Acetphenone by sodiumborohydride (NaBH4). Since, both the reagent and substrate are achiral (optically inactive) and also the reaction takes place in the medium of methanol (achiral), hence, equal amount of (R)-1-phenylethanol and (S)- 1-phenylethanol (racemic mixture) is formed. O HO H HO H CH3 NaBH4 CH3 CH3 + Achiral reagent Acetophenone (S)-1-phenylethanol (R)-1-phenylethanol (Achiral) 50% 50% Example 32: However, when the above reaction is allowed to proceed in the presence of a chiral reagent the (S)-1-phenylethanol is formed preferentially over (R)-1-phenylethanol. O HO H HO H H2 gas CH3 CH3 + CH3 chiral Ruthenium Acetophenone complex (S)-1-phenylethanol (R)-1-phenylethanol (Achiral) 97.5 ee 2.5 ee Some more example of asymmetric synthesis in presence of chiral reagents is shown in figure. H CH3 H CH3 H2 gas COOH COOH + COOH MeO chiral Ruthenium MeO MeO 2-(6-methoxynaphthalen- complex (R)-2-(6-methoxynaphthalen- (S)-2-(6-methoxynaphthalen- 2-yl) acrylic acid 2-yl)propanoic acid 2-yl) propanoic acid 97.0 ee 3.0 ee O O H2 gas HO H O HO H O + OMe chiral Ruthenium OMe OMe complex (R)-methyl 3-hydroxybutanoate (S)-methyl 3-hydroxybutanoate 98.5 ee 1.5 ee Figure : Examples of asymmetric synthesis STEREOSPECIFIC AND STEREOSELECTIVE REACTIONS: Stereospecific reactions: Stereospecific reactions or synthesis are those reactions in which a particular stereoisomer reacts with given reagent to give one specific stereoisomer of the product. This property is called stereospecificity. Thus each individual stereoisomeric substrate under stereospecific synthesis gives a different isomer of the product. Example 33: For example, anti addition of bromine to cis-2-butene gives racemic mixture of 2,3-dibromobutane, while the anti addition of bromine to trans-2-butene gives meso-2,3- dibromobutane. These kinds of reactions are called stereospecific because different stereoisomeric substrate leads different stereoisomeric products.  Example 34: For example, syn addition of meta-chloroperbenzoic acid (m-CPBA) to cis-2- butene gives cis-2-dimethyloxirane [(2R,3S)-2,3-dimethyloxirane], while syn addition of meta- chloroperbenzoic acid (m-CPBA) to trans-2-butene gives trans-2,3-dimethyloxirane [(2R,3R)- 2,3-dimethyloxirane]. Thus the reaction is stereospecific. Example 35: Another example of stereospecific reaction is also considered as the ring opening freactions of oxirans (epoxides). Hydrolysis of epoxides (oxiranes) obtained by the syn addition of peroxyacid to cis- and trans- alkenes leads to the formation trans- diols (diols = dihydroxy compounds) in which both the vicinal hydroxy groups are trans to each other.  H O H H+/H2O HC CH3 HO OH + HO OH 3 H H H H (2R,3S)-2,3-dimethyloxirane (2S,3S)-butane-2,3-diol (2R,3R)-butane-2,3-diol (cis) (trans diol) (trans diol) H H H O H H+/H2O HO HO OH + OH H3C CH3 H H (2R,3R)-2,3-dimethyloxirane (2R,3S)-butane-2,3-diol (2S,3R)-butane-2,3-diol (trans) (trans diol) (trans diol) Stereoselective reactions: Stereoselective reactions or synthesis are those reactions in which one stereoisomer (or one pair of enantiomers) is formed predominantly or exclusively out of several possible stereoisomers. This property is called stereoselectivity. In such reactions one stereoisomer is formed more rapidly than other, thus one stereoisomer forms in excess in the resulting mixture of the products. For every stereoselective reaction there is more than one mechanistic path by which reaction may proceed; however, it is observed that the reaction proceeds either via the most favorable path (for which rate of reaction is fast i.e. kinetic control) or via the path that gives the most stable stereoisomer as the major product ( i.e. thermodynamic control). The stereoselective reactions/synthesis or the stereoselectivity can be further subdivided in to two categories, a) enantioselective reactions/synthesis or enantioselectivity, b) diastereoselective reactions/synthesis or diastereoselectivity. a) Enantioselective reactions or enantioselectivity: Enantioselective reactions are defined as the reactions or processes in which one of the enantiomer forms predominantly over the other. This property is known as enantioselectivity. Enantioselectivity is achieved when a stereoselective reaction is performed in the presence of using a chiral environment (i.e. either a chiral substrate, or a chiral reagent, or a chiral catalyst, or a chiral solvent). Example 36: For example, Fumaric acid when hydrolyzed in presence of Fumarase (a chiral enzyme) gives (S)-2-hydroxysuccinic acid exclusively.  O O OH H 2O OH HO HO O Fumarase enzyme OH O fumaric acid (S)-2-hydroxysuccinic acid Example 37: Similalry, reduction of carbonyl group by Baker’s yeast exclusively leads to the formation of S- enantiomer. Examples of reduction of carbonyl groups by baker’s yeast are shown below. O O OH O [H] H3C O CH3 Baker's yeast H3C O CH3 ethyl 3-oxobutanoate (S)-ethyl 3-hydroxybutanoate OH O [H] CH3 CH3 Baker's yeast Cl Cl 1-(4-chlorophenyl) (S)-1-(4-chlorophenyl)ethanol ethanone The Sharpless epoxidation of allylic alcohol in presence of titanium tetraisopropoxide, t- butylhydroperoxide and enantiomerically pure diethyltartrate (DET) gives enantiomerically pure epoxide. The stereochemistry of product depends on the stereochemistry of diethyltartrate. The diethyltartrate is readily available in its enantiomerically pure forms (i.e. R,R and S,S). (R,R)- diethyltartrate (DET) gives (S,S)- epoxide, whereas, (S,S)-diethyltartrate (DET) gives (R,R)- epoxide. Ti(OPri)4 O H HO HO (R,R)-DET, t-BuOOH CH3 H CH3 (E)-but-2-en-1-ol ((2S,3S)-3-methyloxiran-2-yl)methanol Ti(OPri)4 O H HO HO (S,S)-DET, t-BuOOH CH3 H CH3 (E)-but-2-en-1-ol ((2R,3R)-3-methyloxiran-2-yl)methanol b) Diastereoselective reactions or diastereoselectivity: Diastereoselective reactions are defined as the reactions or processes in which one of the diastereomer forms predominantly or exclusively over the other. This property is known as diastereoselectivity. Diastereoselectivity is usually achieved through in the presence of steric hindrance. Example 38: Let us consider the conjugate addition of lithium dimethylcuprate [(CH3)2CuLi] to 4-methylcyclohexenone. In this reaction cuprate reagent has equal possibilities to react from the either faces of the 4-methylcyclohexenone; however, the bulky cuprate reagent prefers to approach from the less hindered face (i.e. opposite to the methyl group) of the 4- methylcyclohexenone. As a result one diastereoisomer (i.e. trans- product: methyl groups are trans- to each other) out of two possible diastereoisomers forms in excess. Thus, this reaction is called diastereoselective reaction. O O O (i) (CH3)2CuLi + (ii) H /H2O CH3 CH3 CH3 CH3 CH3 (S)-4-methylcyclohex- (3S,4S)-3,4-dimethyl (3R,4S)-3,4-dimethyl 2-enone cyclohexanone (98%) cyclohexanone (2%) Example 39: Another example of diastereoselective reaction/synthesis is the epoxidation of cyclic alkenes with peroxyacids. In such reactions the epoxidation also takes place from the less hindered face. Epoxidation of 4-methylcyclohexene by peroxyacetic acid gives 80% addition product from the less hindered face (i.e. opposite to the methyl group) and 20% addition product from the more hindered face (i.e. from the face of methyl group). H CH3COOOH H O + H O H3C H3C H3C (S)-4-methyl cis-epoxide 20% trans- epoxide 80% cyclohex-1-ene CONFORMATIONAL ANALYSIS OF ALKANES The different spatial arrangements of atoms in a molecule which is readily interconvertible by rotation about single bonds are called conformations. The study of various preferred conformations of a molecule and the correlation of physical and chemical properties to the most preferred conformer is called conformational analysis. Due to rapid interchange of the spatial positions of groups/atoms these conformers are non-separable under normal conditions. Since, different conformations arises because of the rotation about single bonds, hence, they are also called the rotamers. The conformational and configurational isomerisms are related to energy barrier for interconversions of different spatial arrangements of atoms in a molecule. If the energy barrier for interconversion of different spatial arrangements is between 0.6 kcal/mol-16.0 kcal/mol; it result the conformational isomers or conformers; whereas, if this energy barrier is more than or equal to 16 kcal/mol than the configurational isomers are obtained. CONFORMATIONAL ANALYSIS OF ETHANE: When ethane molecule rotates around carbon-carbon single bond, two extreme conformations (one is highly stable and other is highly unstable) are obtained. The highly stable conformation of ethane is called ‘staggered conformation’ and the highly unstable conformation of ethane is called ‘eclipsed conformation’. In between these two extreme conformations (i.e. staggered and eclipsed), an infinite number of conformations are also possible. Staggered conformation: A conformation with a 60° dihedral angle is known as staggered conformation. The angle between the atoms attached to the front and rear carbon atom is called dihedral angle. Eclipsed conformation: A conformation with a 0° dihedral angle is known as eclipsed conformation. In staggered conformation the atoms are located at maximum possible distance from each other hence they are in their most relaxed spatial arrangement thus the staggered conformation is considered as the most stable conformation; whereas, in eclipsed conformation the atoms are located at minimum distance, hence due to repulsion between the atoms the eclipsed conformation is considered as the least stable (high energy) conformation. There are two methods for the representation of staggered and eclipsed conformations, a) the Sawhorse representation formula and, b) the Newman representation formula. a) The Sawhorse representation formula: In sawhorse representation formula the spatial arrangement of all the atoms/groups on two adjacent carbon atoms. The bond between adjacent carbon atoms is represented by a diagonal line and rest of the atoms are located on each carbon at +120° or -120° angles to each other. The sawhorse representation is shown as: diagonal line H H H H H OR 120o H H 120o H viewpoint H H H H viewpoint Sawhorse representation formula b) The Newman representation formula is a planar representation of the sawhorse formula. The molecule is viewed along the axis of a carbon-carbon bond. The carbon atom in front of the viewer is represented by a dot (), whereas the carbon atom away to the viewer is represented by circle. The rest of the atoms/groups are located on each carbon atoms at +120° or -120° angles to each other as shown below: The different conformations of ethane are not equally stable. The staggered form in which the hydrogen atoms are ‘perfectly staggered’ (dihedral angle is 60°) is the most stable conformation. This is because, in this conformation the all carbon hydrogen (C-H) bonds are located at maximum possible distance to each other, and hence they feel minimum repulsive energy from each other. In eclipsed conformation of ethane, the hydrogen atoms attached to each carbon are directly opposing to each other. This result the minimum separation of the atoms or groups, and hence they feel maximum repulsive energy from each other. The eclipsed conformation therefore, of highest energy and has the lowest stability. A graph plot for the energy profile for various conformations of ethane is shown on figure. The relative stability of various conformations of ethane is Staggered >> Eclipsed Figure : Energy profile diagram of conformational isomer of ethane  CONFORMATIONAL ANALYSIS OF N-BUTANE: n-Butane (C4H10) has three carbon-carbon single bonds (Figure); therefore the molecule can rotate about each of them. The rotation about C2 and C3 bond will provide the symmetrical conformations. To study the conformational analysis of n-butane, we must consider it as a derivative of ethane molecule, where one hydrogen at each carbon of ethane is replaced by methyl group (-CH3). H H 1 4 H3 C C C CH3 2 3 H H Figure : Butane molecule Various conformation of n-butane can be obtained by rotation about C2 and C3 bond are shown in figure : Figure : Energy profile diagram of conformational isomer of n-butane From figure , we can see that n-butane has three staggered conformations (I, III and V). Conformer I, in which two methyl groups are as far as possible, and hence is more stable than other two staggered conformers (i.e. III and V), because conformer I, has minimum repulsive energy. As you can see from figure; in conformer I, both the methyl groups are located opposite to each other. The most stable conformer of n-butane, in which both the methyl groups are located opposite to each other is called the anti-conformer, whereas other two staggered conformers (i.e. III and V) are called gauche conformer. Due to difference in steric strain (repulsion between dihedral atoms/groups) the repulsive energy of anti and gauche conformers are also different. Three eclipsed conforms (II, IV and VI in figure) are also exits for n-butane,in which the dihedral atoms/groups are in front of each other (i.e. dihedral angle is 0°). The fully eclipsed conformer IV, in which the two methyl groups are closest to each other, has maximum steric strain; hence it is of higher energy than the other eclipsed conformers (II and VI).Thus the relative stabilities of the six conformers of n-butane in their decreasing order is given as follows: Anti > Gauche > Eclipsed > Fully eclipsed I III and V IV II and VI CONFORMATION OF CYCLOHEXANE: It is known to you that in cycloalkane, all the ring carbons are sp3 hybridized, hence must have tetrahedral geometry with all bond angles of 109.5°. But to sustain its cyclic structure the cycloalkane could not be able to maintain the bond angle of 109.5°. As a result there is a deviation from the normal tetrahedral bond angle. This deviation leads the development of strain in the molecule. Thus the cycloalkanes exhibit angle strain, due to which cycloalkanes are not as stable as their non-cyclic homolog. To minimize the angle strain the structure of cycloalkane is keep on changing from one cyclic form to another which are readily interconvertible by rotation about single bond. This is the reason why cyclohexane and larger rings are non-planar. Cyclohexane exists in two readily interconvertible forms which are called the chair and boat conformations of cyclohexane (Figure). 1 4 2 4 3 3 1 6 2 5 5 6 Chair Boat Conformation of Conformation of cyclohexane cyclohexane Figure Two readily interconvertible conformations of cyclohexane Both chair and boat forms are free from angle strain. In chair form carbon C1, C3 and C5 are in one plane and carbon C2, C4 and C6 are in different plane. Similarly, in boat form carbon C1 and C4 are in one plane and carbon C2, C3, C5 and C6 are in other plane. The interconversions of chair to boat and boat to chair via various other intermediate conformations are shown in Figure. The chair conformation (I and V scheme 1) is considered as a rigid conformation of cyclohexane in comparison to boat conformation; because during interconversion from chair to boat conformation, some angular deformations are required. These I II III IV Chair Half chair Boat Half chair V II A III A Chair twisted boat Twisted boat angular deformations usually increase