CH3 OH Isomers that contain different CH3 CH3 Constitutional Isomers functional groups H3C O H3C Differ in the order of attachment of (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 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 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 of interconversion is interconverted by a bond 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


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 , 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



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 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


Trans-Decalin Cis-Decalin Using dash and wedge to represent bridgehead 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 with extended carbon chain in continuous trans conformation

2) Orient the molecule so the are directed toward the viewer


** 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



145 Fischer Projection

Important Points

- Crosses are always pointing out of the page

- Extended chain is directed away from the page



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 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


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

In this method the substituents are “ranked” by priority

To rank priority: 1) Consider the atomic number of the directly attached (higher the atomic number, higher the priority) 2) For , atomic 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 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 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


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

-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-

-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)



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


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- 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 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 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-

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-

156 Other Stereochemical Descriptors

In sugars and steroids, another common used is the α or β terminology

In sugars the open chain form can form a hemiacetal by reacting with a

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 the anomeric carbon) which can place the new OH group either above the plane of the ring (β ) or below the plane (α isomer)

HO -Cholestanol 3α 157 Other Stereochemical Descriptors

Another term that is used to distinguish two diastereomers is epimer

When two compounds with multiple chiral centers differ in the configuration at only one chiral center (thus would be diastereomers), the two compounds are called epimers (the carbon site would thus be the epimeric carbon)

Consider two again Differ at only one OH Anomeric OH carbon site O carbon O HO HO HO OH OH OH Epimeric OH carbon OH β-D-glucopyranose β-D-allopyranose

If more than one carbon site changes configuration, then compounds are not called epimers If all chiral atoms change configuration then would be enantiomers If some other combination of centers change configuration then would have diastereomers

158 Other Stereochemical Descriptors

Another stereochemical term refers back to the structure of open chain aldotetroses in a Fischer projection


CH2OH CH2OH D-Erythrose D-

In Erythrose, the two higher priority substituents (OH groups) are on the same side of the Fischer while in Threose the OH groups are on the opposite side of the Fischer projection

In other structures with two chiral atoms, if the two higher priority substituents are on the same side of the Fischer, then it is called an erythro isomer while if on opposite sides it is a threo isomer CO H Br O 2 (would still need R and S to know if H N H 2 amino and bromine are on right or OH Br H left side of Fischer) H2N Ph Erythro-2-amino-3-bromo-3- 159 phenylpropionic acid Stereochemical Relationships

The stereochemical relationship between two stereoisomers determines the relationship in physical properties between the two compounds

Enantiomers must have the same physical properties (e.g. melting point, boiling point, solubility, etc.)

Diastereomers, on the other hand, can have quite different physical properties

Same is true for mixtures of stereoisomers Consider a phase diagram representing a molar fraction of different stereoisomers

Enantiomeric mixture Diastereomeric mixture R S R,R R,S

Solubility Solubility

N N The racemic need not be identical to pure R, With diasteromers, the physical properties 160 but the shape must be symmetrical can be quite different Stereochemical Relationships

One way to distinguish between enantiomers is the

If the rotation occurs in a clockwise rotation it is labeled as (+) [a smaller case d is sometimes used to distinguish from capital D in sugars or amino acids (both mean dextro)]

Labeled (-) if counterclockwise (or l from levro)

Chiral compounds will rotate plane polarized Achiral compounds do not rotate plane polarized light Enantiomers rotate plane polarized light the exact same amount, but in opposite directions 161 (or optical purity)

For many cases where there is an abundance of one enantiomer relative to the other the sample is characterized by its enantiomeric excess (e.e.)

The enantiomeric purity is defined by this e.e.

[(R – S) / (R + S)] (100%) = e.e.

Therefore if a given solution has 90% of one enantiomer (say R) and 10% of the other enantiomer (S) then the enantiomeric excess is 80%

[(90 – 10) / (90 + 10)](100%) = 80%

162 Prochirality

Sometimes replacement of one from an achiral center generates a chiral center (this ligand is thus called prochiral)


Ligands (substituents) present in a molecule which when substituted independently generate identical molecules

H2 H1 Substitute H1 H2 D HO OH HO OH

Identical compounds

are obtained D H1 Substitute H2 HO OH

The H1 and H2 substituents are considered homotopic, and are not prochiral

163 Prochirality

Hetereotopic substituents


HO OH Substitute H1 HO OH

H1 H2 D H2 Enantiomers H is therefore H is therefore 1 2 are obtained called pro-R called pro-S (S) HO OH Substitute H2

H1 D

H1 and H2 at this position are called enantiotopic (enantiotopic substituents have the same chemical shift in a NMR)

H1 and H2 will have different environments when placed in a chiral field (e.g. ), therefore need to be able to name the two positions unambiguously

Prioritize substituents using C-I-P naming scheme assuming one prochiral position is prioritized higher than other 164 Prochirality

Hetereotopic substituents

(S) (R) HO OH Substitute H1 HO OH

H1 H2 D H2 Diastereomers H is therefore H is therefore 1 2 are obtained called pro-R called pro-S (S) Substitute H2 HO OH

H1 D (S)

H1 and H2 at this position are called diastereotopic (diastereotopic substituents have different chemical shifts in a NMR)

The chemical environment is different for the H1 and H2 hydrogens (thus why they are diastereotopic and not enantiotopic), therefore they will each have a different chemical shift and they will split each other

165 Prochirality The differences in electronic environments for the heterotopic hydrogens can be used to distinguish isomers


H1 H2 H1 H2

In this , H1 and H2 are In this , H1 and H2 are diastereotopic (the electronic environment of homotopic (the electronic environment of H1 H1 pointed towards both OH groups is and H2 are identical due to a two fold axis), different than H2 pointed away from OH therefore they will split H3 the same groups), therefore they split each other and

will split H3 with different coupling

Signal for H3 in stereoisomers

166 J.-P. Despres, C. Morat, J. Chem. Educ., 1992, (69) A232-A239 Prochirality

Can use diastereotopic hydrogens to distinguish chirality

O O O R Chiral ester R OH O H OCH HS HR HS HR 3

HS and HR are enantiotopic HS and HR are diastereotopic (same signal in NMR) (different signal in NMR)

What if one of the α-hydrogens in the acid is replaced with a stereoselectively, but do not know which one


1 Synthesize the chiral ester and take a H NMR to distinguish 167 Prochirality Blast from the past! (Old scheme from Biewer’s thesis!)


D2O HgCl2 Wittig S S O D O D D OEt




HF/PYR TsO D LAD D D OH OH TsO H D How do we know that this D JONES D O chirality of the α-deuterated OH acid was obtained? H D 168 Prochirality

Had to form chiral ester, and then take NMR


Pro-S O D D O R O H OCH HS HR 3 With this chiral ester it is known that the Pro-S hydrogen is always shifted more upfield O D D O R O H OCH HS D 3

In the stereoselective α-deuteration, the more upfield position remains and thus the pro-S hydrogen remains 169 Prochirality

Prochirality can also refer to trigonal centers (which must be achiral) that become chiral after a reaction

The most common case for organic compounds concerns reactions at carbonyls

O RMgBr OH OH CH or R H CH3 H 3 H R CH3 sp2 hybridized If R is different than

carbons are achiral CH3, then chiral

Depending upon which face the Grignard reacts, two enantiomers are obtained

Naming is a result of the face of approach for the nucleophile 1 1 O O O 2 3 3 2 H3C H H CH3 R HCH3 R Si face Re face (first two letters of Sinister) (first two letters of Rectus) 170