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CHEM 73/8311 CS2 Stereochemistry Conformation Stereoselectivity.docx 2012Jan18 Page1

Stereochemistry
stereoisomers - atomic connections are the same but 3-dimensional structures different
optical activity - rotation of plane polarized light
concepts for chiral compounds
1. stereoisomers not superimposable on mirror image, unique, mirror images are
enantiomers

enantiotopic (http://www.iupac.org/goldbook/E02083.pdf)
“Constitutionally identical atoms or groups in molecules which are related by symmetry elements of
the second kind only (mirror plane, inversion centre or rotation–reflection axis). For example the
two groups c in a grouping Cabcc are enantiotopic. Replacement of one of a pair of enantiotopic
groups forms one of a pair of enantiomers. Analogously, if complexation or addition to one of the
two faces defined by a double bond or other molecular plane gives rise to a chiral species, the two
faces are called enantiotopic.

2. enantiomers have identical physical and chemical properties except with asymmetric
entities
3. racemate - equal mixture of enantiomers, not optically active
4. optical rotation:  [ ]lc ,  = observed rotation, [] = specific rotation, l = pathlength in
decimeters, c = concentration in grams per mL, [] depends on wavelength and temperature
http://www.nsm.buffalo.edu/~jochena/research/opticalactivity.html

5. chiral atom not required

(a) four different groups or electron pairs on atom with tetrahedral geometry, (C, S, P, N)
amines invert as fast as 1011 s-1, slowed down by heteroatom (lone pairs) and small ring
(why?)
(b) restricted rotation of disymmetric planes - biphenyls, allenes, spyro compounds both
sides must be unsymmetrical
H
H3C
H3C H
H CO2Me C C C
Cl H
H CH3
NC CO Me H
N 2 N
O
OMe Me CH3
(c) restricted conformation/rotation - hexahelicene
(d) metallocenes

Br
H H Fe

6. only a racemic mixture of chiral centers can be created by non-chiral reagents???

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OH OH
O 1. PhMgBr

H CH3 H CH3 H CH3

2. H2O Ph Ph
7. Fisher projection: simple 90 degree rotation in the plane not allowed CHO

8. Cahn-Ingold-Prelog: R and S configuration based on atomic number

HO H
9. more than one chiral center - diastereomers can form: stereoisomers that are
not enantiomers- examples H OH
(a) diastereomers are chemically and physically different
(b) 2n isomers possible, sometimes internally racemic (meso), others are dl HO H

pairs H OH

diastereotopic (http://www.iupac.org/goldbook/D01685.pdf) CH2OH

Constitutionally equivalent atoms or groups of a molecule which are not symmetry
related. Replacement of one of two diastereotopic atoms or groups results in the formation of one
of a pair of diastereoisomers. In the example below the two hydrogen atoms of the methylene
group C-3 are diastereotopic.

Resolution
1. convert enantiomers to diastereomers- derivatize with chiral reagent, diastereomers have
different properties
2. chiral chromatography
3. enantioselective reaction/degradation
4. crystallization
Optical purity
1. % optical purity = 100[]obs/[]max
2. % enantiomeric excess = %R - %S = 100([R] -[S])/([R] + [S])
3. easily determined by NMR using chiral shift reagent or diastereomeric derivatives
Cis-Trans Isomerization (diastereomers)
1. double bonds, E and Z isomers
2. rings - cis and trans substituents (including other rings)
3. single bonds – delocalization in amides

O O
N N

4. bridging rings: endo substituent toward larger ring or other substitutent , exo away
Enantiotopic pairs of groups/atoms – prochiral
1. Enantiotopic ligands- identical groups - replacement of each by a new group gives
enantiomers
2. ethanol, pro-R and pro-S

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H H D H H D
endo
exo
D H H D
exo
H3C OH H3C OH CH3 CH3 CH3
endo H H H
2. diastereotopic ligands - identical groups - replacement of each by a new group gives
diastereomers: terminal alkene? groups near chiral center?
3. prochiral faces - clockwise face is Re and counter clockwise is Si
H H

H3C O O CH3

Re Si
4. stereoselective process - one stereoisomer preferred over another
5. stereospecific - different stereoisomers leads to a different stereoproducts
stereospecific
H3C stereoselective
H3C CH3 CHBr3 H3C Br H CCH CHICH 3 2 3

H H KOC(CH3)3 H KOC(CH3)3 DMSO

H Br

H H3C CH3
H3C H
H3C H CHBr3 H3C Br +
H CH3 H H
H CH3 KOC(CH3)3 H H3C Br
3:1
Asymmetric Synthesis -
1. Asymmetric substrate - induction by chiral center O
M S
(a) Cram's rule - attack of carbonyl rotamer from small side
(b) chiral auxiliary e. g. convert acid to ester with chiral alcohol N
2. asymmetric reagent - sellects prochiral faces or ligands RL
3. asymmetric catalyst
4. polarized light
rotantional barriers
kcal/mol
CH3CH3 2.9
CH3CH2CH3 3.4
CH3NH2 1.98
CH3NHCH3 3.6
CH3OH 1.07
CH3OCH3 2.7
Conformational Analysis
1. conformers - rapid rotation interconvert structures

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2. ethane -2.9 kcal/mol barrier, staggered and eclipsed, average CH interaction is 0.9 kcal/mol
3. butane - gauche - anti = 0.9 kcal/mol, 3.4 and 6 kcal/mol barriers, non bonding interaction of
two methyls = 4 kcal/mol
4. propene - eclipsed 2 kcal < bisected, repulsion of methyl  component with  bond
carbonyl behaves similarly (propanal?)

eclipsed bisected eclipsed eclipsed

H H H H H H H t-Bu H

H H H
H H H H
H H t-Bu H
G = 2 kcal/mol
5. butadiene - s-trans favored, same for acrolein (propenal) but not bulky ketones
H H
H H H O H O
H H
H H H H
H H H H
H H H H
s-trans s-cis s-trans s-cis
cyclohexane - chair, twist-boat
1. substituents often prefer equitorial position to avoid gauche (1,3 diaxial) interactions with ring
examine relative free energies for substitutents: Me, Et, iPr, tBu, OH, COOMe, HgBr
2. multiple substitutents also avoid each other, transannular interaction (cis 1,3)???
3. rapid chair-chair interconversion - makes racemic mixture of conformations

equitorial - axial equilibrium of OR

monosubstituted cyclohexane O
Me 1.8 kcal/mol
Et 1.8
iPr 2.1 O
tBu >4.5
CN 0.15-0.25
CH=CH2 1.7
OR
CO2H 1.35
OH 0.5 (acetone)
OH 0.9 (methanol) H H H
H H H H
HgBr 0 H H H H H
other rings H
Heffect - lone H H H
1. heteroatoms in 6 membered rings - anomeric
H H H pair H - * H
2. cyclopropane –planar, eclipsed, angle strain H H
3. cyclobutane – butterfly, angle strain
4. cyclopentane - envelope and half chair
molecular mechanics

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computer programs use potential energy functions based on simple molecules

optimize conformations, bond angles, lengths of complex molecules
not applicable to molecules with structures not available in potential energy functions
Strain
1. energy difference between actual structure and hypothetical
molecule
2. (heat of combustion of ring compounds)/(# CH 2 groups)
cyclopropane>cyclobutane>cyclopentane>cyclohexane
3. cyclopropane, banana bond, -analogy
(a) sp3 orbitals cannot point along internuclear axis (60 o vs.
109o)
(b) increase p character to decrease interorbital angle, rehybridize to sp 5
(c) orbitals toward H have more s character about sp 2
(d) high p character of orbitals seen in conjugation with bonds
(e) react with electrophilic reagents, Br2 forms 1,3-dibromopropane
H H
H H H H
Br
+ Br2 H
Br
H
H H H H
Angewante Chemie, Int. Ed. 47 (2008) 1107

Journal of Organic Chemistry, 72 (2007) 8597

(f) multiple strained rings: tricyclo[1.1.1.0 1,3]pentane has all bonds directed to one side of
plane

4. medium rings -
(a) cyclohexane - chair has gauche interactions?
(b) 5,7-13 member rings, either trans-annular interaction, large angle strain, or eclipsing
interactions
5. larger rings (>14 members) have no strain
6. cyclopropene - polymerizes at -80 oC, less stable than cyclopropane
7. small rings only have cis double bonds, smallest ring with trans double bond has 8 atoms
Bredt's rule

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double bond does not form at bridgehead unless trans ring has at least 8 atoms

smallest ring with triple bond without strain has 9 carbons

8. steric crowding - restricted rotation move

Baldwin’s Rules
1. exo ring closure - electrons move out of ring
2. endo ring closure - electron move in ring
3. ring closure classified according to geometry
tetrahedral, trigonal, digonal
4. tetrahedral - favored for all exo (endo is rare)
5. trigonal - favored except for 3-5 endo
6. digonal - favored except for 3 and 4 exo
7. rules based on steric requirements of nucleophilic attack

exo endo
N 109 N
180
60
N X N X N C X C X C X

Campbell, Pohlhaus, Min, Ohmatsu,Johnson, JACS 130 (2008) 9180 – 9181

Torsional Effects on Reactivity

1. Small nucleophiles preferentially attack axial to avoid eclipsing of O with equitorial H in TS
2. Large nucleophiles prefer equitorial attack to avoid 1,3 type of interaction

H O Nu O
H axial H equitorial H
H
H O O Nu
H H H
H

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