CH221 CLASS 17
CHAPTER 9: STEREOCHEMISTRY CONTINUED
Synopsis. Class 17 starts by considering, briefly, molecules with many chirality
centers and the physical properties of enantiomers and diastereoisomers. Next,
the stereochemistry of some alkene additions are discussed, followed by a short
account of chirality centers at N and P. Finally, biological reactions are
considered briefly and there is an introduction to the idea of prochirality.
Ribbon structure of horse liver alcohol dehydrogenase
Molecules With More Than Two Chiral Centers
The number of possible stereoisomers increases rapidly with the increase in the
number of chiral centers present, as illustrated in the table below.
No. of chirality centres
Possible (maximum) no. of
stereoisomers
1
2
2
4
3
8
n
2n
Thus, cholesterol, with 8 chirality centers can exist as 256 possible
stereoisomers, but only one of these (shown below) is known in nature. A similar
situation exists for a large number of natural products whose molecules possess
several chirality centers. However, many other natural products exist in more
than one stereoisomeric form, two simple examples being (+)- and (-)-lactic acids
and (+)- and (-)-tartaric acids.
CH3
*
CHC6H13
CH3
*
CH3
*
*
*
*
*
*
HO
Physical Properties of Stereoisomers
In general, diatereoisomers have different physical properties (E.g.
melting/boiling points, densities, IR spectra, NMR spectra, etc), whereas
enantiomers have identical physical properties, apart from the sign of rotation of
plane-polarized light. This is illustrated for meso-, (+)- and (-)-tartaric acids in
Table 9.3 on page 291 of the textbook.
Racemic Modifications and Their Resolution
A racemic modification or racemate is a 1:1 mixture of (+) and (-) enantiomers, so
that the overall optical rotation is zero. Racemates are denoted by the symbol ()
or (d,l). Thus, a sample of ()-sodium ammonium tartrate (racemic sodium
ammonium tartrate), as made and studied by Louis Pasteur, contains 50% (+)enantiomers and 50% (-)-enantiomers.
When a chirality center is created as a result of a chemical reaction, the product
will always be formed as a racemate, in the absence of any chiral influences
(such as a chiral catalyst):
O
HO
+
C
CH3
H
HCN
H
H
C
CH3
C
CN
50%
OH
NC
CH3
50%
This can be a big disadvantage to the synthetic chemist whose desire will be to
produce only the physiologically active form of a natural product or drug. Indeed
the other form(s) will be, at best, inactive and at worst, toxic. So the chemist has
to carry reactions such as the above in the presence of some kind of chiral
influence, often a chiral catalyst or agent. If a chiral influence cannot be found,
then the chemist must resort to resolution of the racemic product.
Resolution is the process of separating pure (+)- and (-)-enantiomers from a
racemate.
Louis Pasteur was the first to resolve a racemate – ()-sodium ammonium
tartrate. He was lucky in that this salt crystallized below 28 oC as separate mirrorimage crystals, one type containing only (+)-enantiomers and the other type
containing only (-)-enantiomers. Thus Pasteur was able to separate them using
only magnification and tweezers. This kind of racemate is called a racemic
mixture. Many other kinds of racemates (E.g. racemic compounds, whose (+)and (-)-enantiomers are in the same crystal type) cannot be separated (resolved)
in this way, but there are many alternative methods of resolution, including
Formation of diastereoisomers
Asymmetric destruction, induction and synthesis
Biochemical methods
Kinetic methods
Chiral chromatography
Resolution of Racemates by the Method of Diastereoisomer Formation
This method involves the reaction of racemates with a compatible chiral reagent
of high optical purity to give a mixture of diastereoisomers. The diastereoisomers
can then be separated by making use of differences in physical properties, such
as boiling points or solubilities. The separate diastereoisomer samples are then
treated with a simple reagent to generate pure enantiomers and to regenerate
the chiral reagent (which is sometimes recycled). In practice, this can be a rather
tedious process, often requiring several runs. The basic principles of the method
are outlined below.
(+)A
(-)A
+
(+)A(+)B
(+)B
Racemate
e.g. an acid
(+ (+)B)
(-)A(+)B
diastereoisomeric salts
with different solubilities
an enantiomerically
pure chiral base
(+)A
+
(+)A(+)B
fractional
crystallization
hydrolysis
(-)A (+ (+)B)
(-)A(+)B
This is illustrated by the resolution of (RS)-lactic acid using the base (R)-(+)-1phenylethylamine.
NH2
COOH
H
HO
H
HO
CR
H
CH3
CH3
C
COO-
R
Ph
NH3+
R
C
H C
H
CH
3
HO
CH3
R
Ph
NH3+
S CH3
C
H
HO
COOH
S CH3
C
-
COO
H
CH3
CR
Ph
diastereoisomeric salts
Stereochemistry of Some Reactions
Most biological reactions and many laboratory reactions yield chiral products.
However, if there are no controlling chiral influences on the reaction, a racemic
modification will result – that is to say, the chiral product will be produced as a
1:1 mixture of both (+) and (-) enantiomers. This general principle is illustrated,
next by considering the addition of HBr and Br2 to alkenes.
Addition of HBr to Alkenes
Addition of HBr to 1-butene gives racemic 2-bromobutane:
Br
HBr
CH3CH2CH
1-butene
CH2
ether
CH3CH2*CHCH3
(+)-2-bromobutane
-
Why this occurs can be seen from the mechanism. The carbocation intermediate
is planar and so reaction with Br- can occur equally from either side of the plane,
via mirror image transition states to give equal amounts of the two enantiomers,
as shown overleaf. Both pathways have the same energy, proceed at the same
rate and are equally likely to occur.
Addition of Bromine to Alkenes
Addition of bromine to achiral non-terminal disubstituted alkenes, like 2-butene, is
similar to the previous reaction, except that bromonium ions (rather than open
cations) are involved in the mechanism and the reaction generates two chirality
centers, not one. The bromonium ion can react equally likely at either carbon
atom with Br- to give a 1:1 mixture of two enantiomeric products, as shown
overleaf. The exact identity of the enantiomeric mixture is determined by the
stereochemistry of the alkene: cis-2-butene gives a different pair of products to
trans-2-butene, as will be seen on examination of the reaction mechanism
overleaf.
CH3
H
CH3
C
C
H
CH3
C
H
CH3
a
Cis-2-butene
path a
+
Br
Br2
H
S
C
S
C
Br
C
H
CH3
b
Br-
Br
path b
R R
C C
H
CH3
Br
H
CH3
H
CH3
Br
(+)-2,3-dibromobutane
-
H
CH3
C
C
CH3
H
+
Br
Br2
C
H
CH3
Trans-2-butene
path a
C
a
H
S
C
R
C
R
C
S
C
Br
CH
H 3
b
Br-
CH3
path b
Br
H
CH3
Br
CH3
H
CH3
H
Br
meso-2,3-dibromobutane
Chirality of Atoms Other Than Carbon
Silicon, nitrogen, phosphorus and sulfur are all frequently found in organic
molecules and they too can be chiral in certain circumstances. The chirality of
silicon is very similar to that of carbon, but the chirality of nitrogen especially, and
also of phosphorus and sulfur is complicated by the ability of atoms to invert their
configurations. For simple amines in particular, because of the presence of a
lone pair of electrons, the energy barrier to inversion is small at normal
temperatures, so that it is impossible to isolate individual enantiomers:
H
C2H5
H
rapid
N
N
C2H5
CH3
CH3
mirror
plane
Inversion at phosphorus and certain sulfur atoms, however, is substantially
slower than inversion at nitrogen, so stable chiral phosphines, for example, can
be isolated, as shown below.
(R)-Methylphenylpropylphosphine
is configurationally stable at 100 oC
P
CH3
Ph
CH2CH2CH3
Chirality in Nature
Although the different enantiomers of a chiral compound have identical physical
properties (apart from the sign of rotation), they usually differ in their
physiological effects – i.e. they have different biological properties. Cells are kept
alive and thriving by a host of interlocking series of reactions (both synthetic and
degradative) that are known as metabolic pathways. For a particular organism,
only one enantiomer or diastereoisomer of two or more possibilities normally
takes part in one particular metabolic pathway. The other stereoisomers are
either inactive or participate in different metabolic pathways. This is because
most of the individual reactions of metabolic pathways involve the creation or
destruction of chirality centers and are catalyzed by protein catalysts called
enzymes. The active sites of enzymes of enzymes are chiral and hence
enzymes generally catalyze reactions only when the substrate (the ‘correct’
enantiomer) ‘fits’ the reaction site:
Even when a particular biological reaction doesn’t take place at the chirality
center as such, the chirality of the molecule is still usually important, because of
the chirality of the enzyme active site. Some interesting examples of the
selectivity of biological processes are to be found overleaf in the sensation of
odor and flavor: different enantiomer, different odor.
(+)-limonene
(-)-limonene
odor of orange
odor of lemon
(+)-carvone
(-)-carvone
O
O
odor of caraway
odor of spearmint
Prochirality
A molecule is prochiral if it can be converted from achiral to
chiral in a single step
E.g.
1.
O
OH
2H
C
CH3
CH3
C2H5
Ph
H
C
Ph
Br2
H
H
COOH
C*
H
+
HBr
2-bromo-2-phenylethanoic acid
3.
H
HOOC
Br
COOH
2-Phenylethanoic acid
C
C2H5
H
2-butanol
2-Butanone
2.
*
C
C
OH H
H2O
HOOC
COOH
cis-1,4-Butanedioic acid
(fumaric acid)
C*
C
H
H
COOH
2-hydroxy-1,4-butanedioic acid
(malic acid)
Which enantiomer is produced in 1 and 3 above depends upon which FACE of
the prochiral unsaturated group undergoes addition. The two faces can be
named using the Cahn-Ingold-Prelog priority rules, as follows.
Similarly, in example 2 above, which enantiomer is produced depends on which
hydrogen atom is substituted at the prochirality center carbon atom:
Many biological reactions involve prochiral compounds being converted to a
single enantiomer product, two prominent examples are given below.
H
re
C
-
OOC
C
si
H2O
fumarate
hydratase
-
COO
-
OOC
C
in TCA cycle
H
reaction at
si face
CH2COOH
OH
(S)-malate
Fumarate
-2H
yeast alcohol
dehydrogenase
OH
C
CH3
H
HSR
O
C
in yeast alcoholic
fermentation
CH3
HS
removal of pro-R
hydrogen only
Class Questions
1. Identify the indicated faces in the following molecules as re or si.
2. Lactic acid buildup in tired muscles results from the reduction of pyruvate.
If the reaction occurs at the re face, what is the stereochemistry of the
product?