Chapter 5 – Stereochemistry/Stereoisomerism

isomers

constitutional stereoisomers

(same composition, (same composition,

different connectivity) same connectivity,
different 3D structure)

cis/trans is one subset

Recall, for cyclic compounds:

and I
cis trans

1
Also, double bonds where each sp2-C is bonded to one H:

Ci ci no dipole
and Different compounds

417 d H
with different proper>es
(i.e., b.p.).
cis or E
trans or E

E/Z System for Alkenes

*beCer (less ambiguous) system for assigning configura>on

How to determine?

1) Look at groups on each sp2 carbon and assign priority

(based on atomic #; higher # = higher priority).

Ex. on the
if higherpriority groups are
same side then designate molecule

I_1H
F
N 2
z
if higher priority
zamezide
groups are on
the

sides designate E
saffe opposite
z
2
 E priority groups are

Ex. on the opposite side

2) If there’s a >e in atomic #, go to next atom priority.

Ex. BC
Cl Gtz
Ctf CH CHz
Z
c

CI É CHz OH

3
3) If the molecule has mul>ple bonds (i.e., double or triple bonds), treat like the atom is bonded to
that number of those atoms.

Ex.
to CHz o
higherpriority CH
É e e c CCH
priority

EIFI
HO
cti.tt
CHH
É Ed c c
ct's cts
H E
C
CEC C

Ex.
morecarbon
C CIHH
Cl

LET
c Cltic

MMTrbon
4
4) Isotopes – higher mass gets higher priority (i.e., D > H)

Ex.
H E

IF

Chirality (handedness)

Look at two hands:

- mirror images
- nonsuperimposable
Chiral = something that has a nonsuperimposable mirror image

Achiral = not chiral (has a superimposable mirror image and a plane of symmetry)

Molecules can be chiral: these are nonsuperimposable

Br mirror images
Pr
e
H
tri CHz
i
as Iii
CI 5
i
Enan>omers: – type of stereoisomer
– nonsuperimposable mirror images

*any chiral molecule has 2 enan>omers and ONLY 2

Shortcut to tell if a molecule is chiral:

Look for “chirality center” which is a type of “stereogenic center”.
*sp3 carbon with four different groups aCached
Ex.
Br

H
CHS
a

If only one C*, chiral (always)

If > one C*, maybe chiral (see later)

Stereogenic center = an atom where the interchange of groups results in a stereoisomer. Note that
stereoisomers are not necessarily chiral (i.e., cis/trans alkenes are stereoisomers but are not chiral)
but chirality centers are stereogenic centers.

6
Let’s examine the following molecule:
flip

we win
ME and

Tantiomers
Inon superimposable mirrorimages
Name? Same as before. Both are:
3 methyl hexanes
How to specify which enan>omer?

R/S ConvenFon
a) Assign priori>es to all four groups
b) Put lowest priority group in “back” (dashed wedge bond)
c) (clockwise) 1-2-3 Þ R
(counterclockwise) 1-2-3 Þ S

d) Put (R)- or (S)- in front of the name

From above we have: mmmm

need to assignpriorities to
which
is
find which structure

7
How to assign priori>es? Based on atomic #.
Look at atomic # of atoms connected to C*.
Higher atomic # = higher priority

Ex. 2
Cl
ccw S
HLionestpriority
A
3 H 3C Br
higher atomic

Ex.
CH3 H is always lowest priority when
ow R present
4 H
F
H 2N
I
2
Isotopes = higher mass = higher priority (i.e., H vs D)
until
Methyl vs Ethyl. How to differen>ate between carbon chains? longer chains are priority
Keep going down the chain un>l a point of difference. theres a tie breaker

8
 number
higher atomic
i.e.,
higher priority

d1 n ItH H
C CHH
H CHHH

methyl
ethyl
In fact, any one atom of higher atomic # has priority.

So, higher atomic

a
S H O H
d H VS d o H
1 c HHS
one beats two H C Hoo
Double bonds count twice (triple = 3).
So, Carbon is bonded

f
f
counts as to Oxygen twice
a e
H oxygen is bondedto
carbon twice

C OOH
2 O's beat one 9
0
 find the chirality centre

Let’s assign R/S to serine and cysteine.

as sulfur wins
4 3 4 C SHH
H CH2OH H CH2SH

OH OH
1 H 2N
ES tnthis carbon I H 2N 3
C 000
O
is connected
to threeoxygen O
S serine
R cysteine

Draw enan>omers of these:

- two ways to do this easily

the chirality centre

invert
the
is alr flip 3 0H

12N jo 0H assumed
asthe
wedge
Hoyt 2

R serine
R serine

10
other way draw mirrorimage

cannot do both
 sometimes lowest priority is not in the back
attached to it
Stereogric centre alwas have 4 groups

Ex.
OH

H
H maid s

24p tie breaker

not a stereogenic
centre don't be
fooled by wedges for cyclohexane draw it
dashes as a hexagon when
OpFcal AcFvity assigning

Enan>omers have same physical proper>es (mp, bp, d, solubility).

So, how to tell them apart?

They can have different proper>es with a chiral material.

Ex. handshake right-right = okay

right-leb = awkward!

11
Enzymes (chiral) can tell the difference (spa>al recogni>on).

Ex. 6024 de

no.it I 40
21
R lacticacid
5 lactic acid pyruvate

You can (some>mes) tell the difference.

Ex.

O O

H H

R carvone
s carvone

12
 15 ibuprofen active
Ex. H CO2H
IR ibuprofen inactive
Etienne

We can use a technique called polarimetry to see if sample is “opFcally acFve”.

To do this we plane-polarize the light (this is how polarized sunglasses work) then pass the light
through a chiral sample then look at the angle of rota>on of the light.

If the light rotates clockwise: dextrorotatory (d or D)

If the light rotates counterclockwise: levorotatory (l or L)

The extent of the rota>on (degrees = °) depends on four things:

Wavelength (l), path length, concentra>on, and temperature

To makes things consistent, we determine the specific rota-on using the following equa>on:

∝
!"#$%&%$ ()*+*%), = [∝]"#
! = %'(

13
Ex.

3 13.5
α 13.5
R E 2 butanol
s F 2 butanol

Key notes: out

a) NO correla>on between R/S and +/–!!
Cannot tell from geometry if (+) or (–)

b) Enan>omers have equal magnitude, opposite sign

c) Two ways to be “op>cally inac>ve” (i.e., no rota>on)

i. Achiral, ex. [a] = 0

ii. 50:50 mixture of enan>omers

“racemic mixture” or “racemate”
ex. ( )-2-butanol Þ each enan>omer in equal amounts so the rota>on
cancels out ® [a] = 0

equal amounts of R S
14
d) If only one enan>omer, “op>cally pure” or “enan>omerically pure” (i.e., as men>oned above,
enan>omerically pure (S)-(+)-2-butanol has [a] = 13.5°)

e) Can have mixtures beyond 50:50 – i.e., we can have an “enan>omeric excess” of one
enan>omer over the other. For 2-butanol, if we have an enan>omeric excess if we see a
rota>on of <13.5° but more than zero.

ex. 75% (+) and 25% (–)

)*+,-.)/0,-
Enantiomeric excess (ee) = ()*+,-2)/0,-)
' 455%

("#$%#)
So, a 75:25 mixture has !"##% = 50% ee
("#'%#)

! .
This is an outdated method but it correlates to [∝]"#
i.e.,
,789-:9; [∝]
%## = >?-9 90*0@/,)9- [∝]
'455%

50 0.5 13.5 6.75

ee

15
EnanFomers and Diastereomers

isomers

constitutional stereoisomers

(same composition, (same composition;

different connectivity) same connectivity;
different 3D structure i.e., nonsuperimposable)

enantiomers diastereomers
“mirror images” (no mirror images)
i.e., cis/trans

Diastereomers: stereoisomers that are NOT mirror images

Already know:
and

cis trans

16
Diastereomers also arise with >1C* (stereogenic center).

Ex.
Br Cl of stereoisomers possible
2 where n of c
H 3C C* C* CH3

H H 2 c here 22 4
2-bromo-3-chlorobutane

Let’s draw: Mirror Minor

β D
Mt
A a Br Br Cl

for
B

Tete i Fantini
3R
trial I
Ii
2R 35 25 2 R 3R 1 25,35

enantiomers
IE
of eachother
non superimpressable
mirror images 17
Note: every C* is the opposite when drawing enan>omers (i.e., every stereogenic center is
inverted).

Q: Rela>onship between B and C?

2R 3R diastercomers
A: β 25 3R C

Note: at least 1 C* is the same

at least 1 C* is the opposite

Ex.

23 8
8possible stereoisomers

171,104
CH I L

zyY4
CI
enantionersftt
IE jy
di smon

18
 Meso Compounds

Recall, 0 C*, usually achiral

1 C*, chiral (always)
2 C* (or more), maybe chiral

Look out for meso compounds!

TThmage – have chirality centers but the overall molecule is achiral
– usually have a plane of symmetry
EEE
Ex.
achiral
h engf
CI a 4 a

H.tt oisla
ii H3C ift
mtaai EEEE.in

meso

19
 What about the following molecules?

tf.ir
Cl

11 it c

fF.ca
Cl

spimposane nonsuperimposable

vs
chiral

Cl
Iast pod

Era
ppl
plane
Stymmeting Cl

siphy
superimposine
is
quest achiral meso

achiral

20
Fischer ProjecFons

It’s another way to draw molecules (especially useful for many C*).

Ex.
H
OH OH O
TO
HO H OH
6 5 4 3 1 1 H

OH OH

glucose (acyclic form)

I 6
OH

It’s how to easily compare different diastereomers (*different sugars).

How to do it:

1. Put the longest C–C–C chain in a ver>cal line. These represent dashed wedge bonds ( ).
2. Put subs>tuents on horizontal lines. These represent solid wedge bonds ( ).
3. Remove and bonds and replace with regular lines. (Note: these s>ll represent things
going out of the page and into the page, respec>vely)
it
can't flip but can spin
21
Ex. CH3CH(OH)CH3

Ctb implied its going

13 apack dashedwedge

arc at 0H H OH

implied its going out

ÉH
solidwedge
cots
fiscffection
Ex.

cats

H C
Ft Cac

to_ an to H
Hoo a Br
H BV
ÉH3
CMs
fischer
projection 22
Fischer projec>ons make comparison easier.

i.e.,

CH3 vs CH3
I
vs CH3

H Cl Cl H Cl H

HO H i H OH H OH
switched only
1
H Br Br H
i H Br
one
CH3
i CH3 CH3 restraint
centre
nonsuperimportle
mimerimages
enantiomers
diastereomers

Note: It is important to remember that horizontal bonds are implied and ver>cal bonds
implied . Therefore, you CANNOT flip a Fischer projec>on like a pancake. You can ONLY rotate
the molecule 180° in the page.

23
 How to assign R/S?

H O
2
C
LEO
4H C OH
I oscar
CH2OH 9
3 Ct2OH
Holgoon
inventing
a dash
You can rotate 3 groups and hold 1 group fixed to put the lowest priority group into the back (i.e.,
put the lowest priority group on a dashed wedge bond .

i.e.,

go I
so

ino Fessit 3
no 8120

H
H
4 24
ResoluFon of EnanFomers

Recall, enan-omers are the same energy (same physical proper>es). In many cases, a reac>on to
produce a chiral compound will produce a racemate (unless using help from something chiral; i.e.
chiral solvent or chiral catalyst).

i.e.,

O OH + OH
NaBH4

How to separate the enan-omers? Not easy! They have the same proper>es.

However, we know that diastereomers have different physical proper>es and can take advantage of
this.

First “resolu>on” in 1847 by Louis Pasteur. He no>ced that the crystals of tartrate salts were
different (nonsuperimposable).

25
 CO2 Na CO2 Na

H C* OH HO C* H
+
HO C* H H C* OH

CO2 NH4 CO2 NH4

(R,R) (S,S)

More common these days is to exploit the difference in behavior that

enan>omers have with chiral material.

1) Pass through a column packed with chiral material – called “column

chromatography”. One enan>omer “s>cks” to the chiral material more
(orange) than the other enan>omer (purple).
2) React with enan>opure chiral material to make diastereomers. Now they
have different proper>es and can be separated more easily using
crystalliza>on, dis>lla>on, chromatography, etc.
NH3 O2C OH
NH2

HO2C OH NH3 O2C OH

NH2 (R,R) (R,R)
(R,R)
+ +

NH2
HO2C OH NH3 O2C OH
(R,R)

NH2
(S,S) NH3 O2C OH
(S,S) (R,R)

26
3) Some chiral catalysts or enzymes react with one enan>omer and leave the other behind (recall
earlier example with lac>c acid). This is called kine>c resolu>on.

4) Asymmetric synthesis (very hard and important field of chemistry where we try to only make
one enan>omer over the other).

Chiral Centers other than Carbon

Other atoms can have tetrahedral geometry and thus be chiral (i.e., Si, Ge, S, N). See PowerPoint
slides for examples.

Other Types of Chirality

Some molecules do not have a chirality center but are s>ll chiral (have nonsuperimposable mirror
images). One example of this is with atropisomers – molecules that have restricted rota>on about a
bond so that two (or more) possible conforma>ons are stable and thus the isomers can be isolated
independently. These possess a type of chirality called axial chirality. Within the class of axial
chirality is a type of chirality called helical chirality (looks like a corkscrew). See PowerPoint slides
for examples of axial chirality. There are other types of chirality seen in chemistry but are beyond
the scope of this course.

27