Stereochemistry Functional Group Isomers CH3 OH Isomers that contain different CH3 CH3 Constitutional Isomers functional groups H3C O H3C Differ in the order of attachment of atoms (different bond connectivity) Positional Isomers CH Isomers that differ by 3 CH3 connectivity, but have same H C H H3C 3 CH functional groups 3 Isomers Have same molecular formula, but different structures Enantiomers H H Image and mirrorimage Br F F Br are not superimposable Cl Cl Stereoisomers Atoms are connected in the same order, but differ H CH3 in spatial orientation Diastereomers H3C H3C Not related as image and CH3 H mirrorimage stereoisomers H H 140 Stereochemistry The types of stereoisomers can in fact be further delineated 1) Conformational Two different conformers of the same compound may have nonsuperimposable mirror images Cl Br The two conformers can be H If the energy of interconversion is interconverted by a bond rotation H H low (< ~20-25 kcal/mol) the two H conformers cannot be separated and thus not considered chiral Br Br H Cl Cl H H H H H H H CO2H HO2C Can also observe with conformational HO2C CO2H enantiomers if the energy to interconvert is O2N NO2 too high NO2 O2N 141 Stereochemistry 2) Configurational Typically when an organic chemist refers to stereoisomers, they generally mean configurational stereoisomers where the two isomers can only be interconverted by breaking a covalent bond (cannot be made equivalent by rotation about any bond) A chiral compound can Enantiomers Br Br have only 1 enantiomer, Nonsuperimposable mirror H H but the number of H3C CH3 image compounds Cl Cl diastereomers is dependent upon number of chiral centers diastereomers Diastereomers Br H Br H H Br Stereoisomers that are not CH3 CH3 CH3 H3C H3C H3C related by a mirror plane Cl H H Cl Cl H With diastereomers, often have multiple chiral centers enantiomers present which yield a variety of stereoisomers 142 Stereochemistry Chiral compounds thus have a three dimensional shape, in order to represent these three dimensional objects in a two dimensional page a number of drawing conventions have been adopted Organic chemists use a wedge and dash line system to designate stereochemistry Wedge line – object is pointing out of the plane Dash line – object is pointing into the plane H H H H To draw a tetrahedral carbon: 1) Make a V with an angle approximately at 109.5˚ 2) Place the wedge and dashed lines in the obtuse angle space Common errors: 1) placing dashed and wedge lines in acute space 2) Placing either two bonds as wedge or dashed with two bonds in plane 3) Placing dashed and wedge bonds on opposite sides of bonds in plane 143 Stereochemistry Another method to represent three dimensional structures is to indicate whether a hydrogen is pointing out of the plane or into a plane by using a solid dot approach (primarily only used in fused ring type structures) H H H H Trans-Decalin Cis-Decalin Using dash and wedge to represent bridgehead hydrogens can become cumbersome (especially as structure becomes larger) H H Another method is to H H A solid dot means represent whether the hydrogen hydrogen is coming out of is coming out of plane plane toward viewer (absence of dot means going into plane) 144 Fischer Projection Another convenient way to represent stereochemistry is with a Fischer projection To draw a Fischer projection: 1) Draw molecule with extended carbon chain in continuous trans conformation 2) Orient the molecule so the substituents are directed toward the viewer CO H HO 2 H CH3 ** Will need to change the view for each new carbon position along the main chain 3) Draw the molecule as flat with the substituents as crosses off the main chain CO2H HO H CH3 145 Fischer Projection Important Points - Crosses are always pointing out of the page - Extended chain is directed away from the page CO2H CO2H HO H HO H CH3 CH3 A Fischer projection can be rotated 180˚, but not 90˚ OH 90˚ CO2H 180˚ CH3 Convention is to place H3C CO2H HO H H OH more oxidized carbon at top, but obtain same H CH3 CO2H stereoisomer A 90˚ rotation changes whether substituents are coming out or going into the page It changes the three dimensional orientation of the substituents 146 Fischer Projection Fischer projections are extremely helpful with long extended chains with multiple stereocenters Orient view at each chiral center H C CH3 3 Br H Br H H H Cl Cl CH 3 CH3 An enantiomer is easily seen with a Fischer projection CH3 CH3 H Br Br H H Cl Cl H CH3 CH3 Merely consider the “mirror” image of the Fischer projection 147 Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms A chiral carbon is classified as being either R or S chirality In this method the substituents are “ranked” by priority To rank priority: 1) Consider the atomic number of the atom directly attached (higher the atomic number, higher the priority) 2) For isotopes, atomic mass breaks the tie in atomic number 3) If still tied, consider the atoms bonded to the tied atoms. Continue only until the tie is broken. 4) Multiple bonds attached to an atom are treated as multiple single bonds. An alkene carbon therefore would consider as two bonds to that carbon 1 Br 2 4 CH=CH H 2 CH2CH3 3 148 Cahn-Ingold-Prelog Naming System for Chiral Carbon Atoms After ranking substituents, place lowest priority substituent towards the back and draw an arrow from the highest priority towards the second priority 1 1 Br 2 Br 3 4 CH=CH 4 CH CH H 2 H 2 3 CH2CH3 CH=CH2 3 2 1 1 Br Br H3CH2C CH=CH2 H2C=HC CH2CH3 3 2 2 3 R S If this arrow is clockwise it is labeled R (Latin, rectus, “upright) If this arrow is counterclockwise it is labeled S (Latin, sinister, “left”) 149 Using Cahn-Ingold-Prelog in Assigning Alkenes -substituents are prioritized Consider each end of the alkene separately -if the highest priorities are on the same side called Z 2 2 H3C H Z – zusammen – “together” 1 Br CH3 1 Z-2-bromo-2-butene -if the highest priorities are on the opposite side called E 2 1 H3C CH3 E – entgegen – “opposite” Br H 1 2 E-2-bromo-2-butene 150 Meso Compounds Sometimes there are compounds that are achiral but have chiral carbon atoms (called MESO compounds) Maximum number of stereoisomers for a compound is 2n (where n is the number of chiral atoms) Enantiomers Diastereomers Identical (nonsuperimposable (not mirror related) (meso) mirror images) CH3 CH3 CH3 CH3 HO H H OH HO H H OH H OH HO H HO H H OH CH3 CH3 CH3 CH3 This compound has only 3 stereoisomers even though it has 2 chiral atoms 151 Meso Compounds The meso compounds are identical (therefore not stereoisomers) therefore this compound has 3 stereoisomers Meso compounds are generally a result of an internal plane of symmetry bisecting two (or more) symmetrically disposed chiral centers CH3 HO H 2,3-(2R,3S)-butanediol has an internal plane of HO H symmetry as shown CH3 Any compound with an internal plane of symmetry is achiral 152 Other Stereochemical Descriptors The R/S designation is used to describe the absolute configuration at a chiral atom There are cases, however, where this does not completely describe the system (especially if the molecule is chiral, but there are no chiral atoms) Have already seen an example of this with a conformational chirality There are no chiral atoms, NO2 but the molecule is chiral Br An example of helical chirality O2N Br In these cases, the viewer looks down the chiral helical axis The substituents are prioritized NO2 Clockwise rotation: on the front and back 1 P (positive) O2N Br Draw a circle from the highest Counterclockwise rotation: priority on front to highest priority Br 1 M (minus) on back (P) chirality 153 Other Stereochemical Descriptors An important point with the helical P/M descriptors is that it doesn’t matter which end of the helical axis the viewer chooses as the end point NO2 NO2 NO2 Br 1 Br NO O N Br 1 2 2 O2N 1 Br 1 Br Br (P) chirality (P) chirality Helical chirality is present in a number of different systems Shown as clockwise rotation, CH3 (P) chirality H3C 1 C C C H H C H CH 3 Cl 3 Cl 1 Allenes (M) chirality α-helix 154 Other Stereochemical Descriptors In bicyclic systems, substituents are labeled as endo or exo describing their orientation relative to the bicyclic system This bicyclic system has a 6-membered Chlorine is towards 6-membered ring, and 5-membered ring while H is away from larger ring H Cl Cl: endo H: exo Endo or Exo refer to position relative to larger ring of bicyclic system Endo: towards larger ring Exo: away from larger ring exo Br endo H H exo HO endo 155 Other Stereochemical Descriptors With sugars and amino acids the designation D/L is often used Name is a result of the Fischer projection for these types of compounds CHO By convention in a Fischer projection, H OH the most oxidized carbon is placed at the top of drawing HO H The chirality of the highest numbered chiral carbon (thus the chiral H OH carbon near the bottom of the Fischer) is labeled D if higher priority H OH substituent is pointed toward the right (from latin dextro- [to the right]) CH2OH or L if pointed to the left (from latin levo- [to the left]) D-glucose Same system is used in amino acids CO2H H N H 2 Naturally occurring sugars have a D chirality, CH 3 while naturally occurring amino acids have a L chirality L-alanine 156 Other Stereochemical Descriptors In sugars and steroids, another common descriptor used is the α or β terminology In sugars the open chain form can form a hemiacetal by reacting with a hydroxy group CHO OH H OH OH O HO H O HO HO HO H H OH HO OH OH OH OH H OH H α-D-glucopyranose CH2OH β-D-glucopyranose This creates a new chiral carbon (called