Concept Check: Topic 1: Conformation Winter 2009 Page 112 Concept Check: Topic 1: Conformation Winter 2009 Page 113 1
STEREOCHEMISTRY Winter 2009 Page 114 We have already covered two kinds of isomerism: Constitutional Isomers (structural isomers) Conformational isomers (different 3D shapes for the same molecule) Winter 2009 Page 115 2
We will now introduce a third type of isomer - STEREOISOMERS If any two compounds are stereoisomers, then they have the same bond connectivity (the same atoms are attached to the same atoms). BUT, the fixed relative arrangement of the atoms in 3D space is not the same. Fixed means that, unless the stereoisomers undergo some type of chemical reaction, they cannot interconvert. Winter 2009 116 Cis-Trans Isomer Result from Restricted Rotation Winter 2009 Page 117 3
Since we have just dealt with looking at substituted rings in the last section, lets look at the issue of groups being on the same side of a ring or on opposite sides and how to name these molecules. On the previous slide we took note of the fact that one form of 1,2- dimethylcyclohexane (A) is not identical to another (B). We need away to distinguish A and B in their names. We say that their RELATIVE STEREOCHEMISTRY IS DIFFERENT A is called cis-1,3-dimethylcyclohexane B is called trans-1,3-dimethylcyclohexane Winter 2009 Page 118 What about the trans molecule C, is it the identical molecule to B? ANSWER: NO! It s the NON-IDENTICAL MIRROR IMAGE Non-identical mirror image molecules are called ENANTIOMERS A and B are stereoisomers, but they are not enantiomers, they are called DIASTEREOMERS. We will now deal with enantiomers in detail and learn how to distinguish between them by name. Winter 2009 Page 119 4
Mirror-image related stereoisomers (ENANTIOMERS) are said to be left-handed and right-handed and occur when a molecule and its mirror image are non-superimposable. Winter 2009 Page 120 Winter 2009 Page 121 5
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Winter 2009 Page 124 Compounds whose mirror images are superimposable are called ACHIRAL. Examples of chiral and achiral molecules: Above all, the chiral examples contain an atom that is connected to 4 different substituent groups. This atom is called an asymmetric atom or a stereocenter (also called a stereogenic carbon atom) Often, asymmetric atoms are marked with an asterisk. Molecules having one stereocenter are always chiral. Winter 2009 Page 125 7
Winter 2009 Page 126 The absolute configuration of an enantiomer is the actual spatial arrangement of the substituent groups around the chiral centers. There is no straightforward correlation between the absolute configuration of an enantiomer and the sign of rotation of the molecule. The absolute configuration of an enantiomer can be determined through single crystal X-ray diffraction analysis or through chemical correlation to a molecule whose absolute configuration has already been determined. Winter 2009 Page 127 8
R-S SEQUENCE RULES FOR STEREOCENTERS A stereogenic carbon has one of two possible arrangements (configurations) of its four different groups and they are mirror images of each other. One form of the stereogenic carbon will be labelled as having R configuration and its mirror image will then be called S configuration. There is a set of rules, called the Cahn-Ingold-Prelog sequence rules, described on the following slides, which we use in order to find out which of the two possible absolute configurations of a stereocenter is R and which is S. Winter 2009 Page 128 RULE 1. We look first at the atoms attached to the stereocenter. An atom of higher atomic number than another has a higher precedence. If you are comparing isotopes, the one with the higher atomic mass has the higher priority. Lets look at an example: AN 1 (4) AN 17 AN 12 (2) (3) (1) AN 35 We would assign the bromine as priority 1, the chlorine as priority 2, the CH 3 group as priority 3 and the hydrogen as priority 4 (your text uses the letters a,b,c,d). Winter 2009 Page 129 9
We then look at the molecule placing the lowest (4 th ) priority group away from us. In the case of the molecule on the previuos slide this gives us the following view: S R We then consider the sense of direction from highest to lowest priority of the three groups facing us. In this case it is anticlockwise, which we Label as S stereochemistry. A clockwise arrangement would be labelled as being of R configuration. For naming the molecule, the S goes in brackets at the beginning and is italicized: (S)-1-bromo-1-chloroethane. The mirror image will then be (R)-1-bromo-1-chloroethane. Winter 2009 Page 130 RULE 2: What if two substituents have the same rank when we consider the atoms directly attached to the stereocenter? We proceed along the two respective substituent chains, atom by atom, until we reach the first point of difference. RULE 3: Double and triple bonds are treated as if they were single, and the atoms that form the multiple bond are duplicated or triplicated as phantom atoms at each end of the multiple bond. Winter 2009 Page 131 10
Mentally (or physically) arrange the molecule so that lowest priority group is pointing away from you and look at molecule with the chiral center eclipsing the lowest priority group. If the molecule is arranged so that going from 1 to 2 to 3 reflects a clockwise direction then you have a R configuration, other wise it is S or sinister orientation. R and S Configurations 1 2 4 3 Counterclockwise S Configuration Winter 2009 Page 132 Winter 2009 Page 133 11
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Enantiomers cannot be distinguished on the basis of their physical properties, such as boiling points, melting points, and densities. Enantiomers interact differently with plane-polarized light and can be distinguished in this manner. When plane-polarized light is passed through a sample of one of enantiomers, the plane of polarization is rotated either clockwise or counterclockwise. The other enantiomer would rotate the light is an equal amount, but in the opposite direction. If facing the light source: Clockwise rotation: enantiomer is dextrorotary (+) Counterclockwise rotation: enantiomer is levorotary (-) This interaction with light is called optical activity and enantiomers are often called optical isomers. Winter 2009 Page 136 Polarimeter Light is electromagnetic radiation that oscillates perpendicular to its direction of motion. A polarizer can filter all but one plane of light. This light is referred to as plane-polarized light. When plane-polarized light interacts with an optically active solution, the plane gets twisted or altered. Winter 2009 Page 137 13
Solutions containing Chiral Molecules distort or twist the plane of polarization of the light either to the left or right. This effect is called optical rotation and the molecule is said to be optically active. Optical activity is measured using a polarimeter. Winter 2009 Page 138 The Specific Rotation [α] of a chemical compound is determined at a specific temperature (T - in Celcius) and wavelength (λ in nm). This value is calculated from the observed rotation and corrected by dividing by the length of the holding cell (l - in decimeters) by the density (d - in g/ml). For compounds that are dissolved in a solution. The concentration is taken into account by using equation B below. Note the concentration (c) is in g/100 ml. T α A) [α] λ = B) l x d T [α] λ = 100α l x c Typical measurements are made using the Sodium D-line at 589 nm 25 [α] 589 = +66.47 25 [α] D = +66.47 Winter 2009 Page 139 14
Winter 2009 Page 140 Morphine Cocaine Penicillin Winter 2009 Page 141 15
COMPOUNDS WITH MORE THAN ONE STEREOCENTRE We will use this topic as a logical starting point for taking a closer look at cycloalkane rings with more than one substituent. Lets consider 1-chloro-3-methlcyclohexane for example: When we consider this molecule in 3D we will quickly realize that there is more than one possible stereoisomer, in fact there are four! Winter 2009 Page 142 If we first just consider RELATIVE STEREOCHEMISTRY, this deals only with whether the chlorine and methyl are on the same side or opposite sides of the ring, referred to as the cis and trans isomers respectively. (1) (2) S R S S cis-1-chloro-3-methylcyclohexane trans-1-chloro-3-methylcyclohexane If we consider absolute stereochemistry, we find and label the stereocenters using R and S. How do you work out these R and S assignments? Winter 2009 Page 143 16
We then realize each of the above isomers have a mirror image enantiomer, giving us, in total four stereoisomers: (1) (1S,3R)-1-chloro-3-methylcyclohexane (2) (1S,3S)-1-chloro-3-methylcyclohexane (3) (1R,3S)-1-chloro-3-methylcyclohexane (4) (1R,3R)-1-chloro-3-methylcyclohexane (1) S R (2) S S (3) R S (4) R R Winter 2009 Page 144 Notice how we can easily predict the various isomers by recognizing that R configuration is the mirror image of S configuration. If we have a molecule with two stereocenters, then the possibilities are: RR RS SS SR For three stereocenters we have eight possible combinations. First we write all the possible combinations that are diastereomers (i.e. not enantiomers): RRR RRS RSR SRR SSS SSR SRS RSR Then we generate the enantiomer of each of these. 2 n isomers Where n = no. of stereocenters Winter 2009 Page 145 17
MESO COMPOUNDS We can, in fact, write a general rule which says that the maximum possible number of stereoisomers for a compound is equal to 2 n, were n is the number of stereocenters. Why do we have to say maximum possible number of stereoisomers?? Because, sometimes we end up with fewer than the predicted maximum as a result of the possibility of some molecules being meso compounds. Meso compounds are compounds that have two or more stereocenters and also have an internal plane of symmetry (an internal mirror plane). We will illustrate this concept with an example on the next slide. Winter 2009 Page 146 Winter 2009 Page 147 18
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Our first example we will use to illustrate a meso compound is to consider all the possible isomers of 1,3-dimethylcyclohexane: S R R R S S σ There are only three isomers, even though there are two stereocenters. The SR isomer has an internal mirror plane, called a σ plane. Consequently, the RS compound illustrated below is the same compound as the SR compound, but turned around 180 o! The meso compound is a diastereomer of the other two, which are a pair of enantiomers. Winter 2009 R S Page 150 STEREOCHEMISTRY IN AMINO ACIDS AND CARBOHYDRATES Stereochemistry exists in natural compounds such as: amino acids, peptides, proteins, DNA, sugars etc Determine how many chiral centers are in the following amino acids and label them R or S. R There are none S Winter 2009 Page 151 20
NUCLEOPHILIC SUBSTITUTION REACTIONS Virtually all reactions fall into one of four categories: substitution, addition, elimination, or rearrangement. Substitution One functional group replaces another Alkyl halides react with a nucleophile to give a substituted product CH 3 Cl + Na + - OH CH 3 OH + NaCl Nucleophile: A species with an unshared electron pair. A reagent that seeks a positive charge. Examples: HO -, RO -, N 3-, CN -, CH 3 S -, :NH 3 Leaving Group: For a molecule to be reactive to substitution the leaving group must be a good one. A good leaving group must be able to leave as a relatively stable, weakly basic molecule, or ion. Examples: Cl -, Br -, I -, H 2 O Winter 2009 Page 152 General reaction: Nu + R X R-Nu + X Nucleophile Substrate Product Leaving Group Some examples: HO - + CH 3 Cl CH 3 OH + Cl - CH 3 O - + CH 3 CH 2 CH 2 Br CH 3 CH 2 CH 2 OCH 3 + Br - Winter 2009 Page 153 21
REACTION MECHANISM Winter 2009 Page 154 transition states starting material intermediates product Transition State: A point on the reaction coordinate at which the potential energy is at a maximum. Intermediate: A potential energy minimum between two transition states. Winter 2009 Page 155 22
Winter 2009 Page 156 Two possible mechanisms for the substitution: 1. Carbon Halogen bond breaks at the same time the carbon nucleophile bond is formed. Everything happens in one step! 2. Carbon Halogen bond breaks first, then the nucleophile attacks. Happens in 2 steps! Step 1 Step 2 Winter 2009 Page 157 23
THE S N 2 (Substitution, Nucleophilic, Bimolecular) REACTION CH 3 Cl + HO - 60 º C H 2 O CH 3 OH + Cl - Mechanism: The nucleophile approaches the carbon from the side directly opposite the leaving group : a backside attack. As the reaction progresses the bonding orbital between the carbon and leaving group weakens. As the leaving group is pushed away, the carbon atom has its configuration turned inside out, becoming inverted. This mechanisms only involves one step, proceeding through a high energy, short lasting transition state. Winter 2009 Page 158 Winter 2009 Page 159 24
Potential Energy Diagram: Winter 2009 Page 160 Stereochemistry in S N 2 Reactions: Since the carbon atom undergoes an inversion in configuration during an S N 2 reaction, there are consequences when the substrate is chiral. Winter 2009 Page 161 25
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Winter 2009 Page 164 THE S N 1 (Substitution, Nucleophilic, Unimolecular) REACTION (CH 3 ) 3 C Cl + H 2 O (CH 3 ) 3 C OH + HCl Winter 2009 Page 165 27
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Stereochemistry in S N 1 Reactions: The carbocation formed is trigonal planar, and thus can react with the nucleophile from the backside or the front side. Winter 2009 Page 170 If the starting material is chiral, a S N 1 reaction will yield racemic products, since the carbocation intermediate is achiral. Winter 2009 Page 171 30
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