Model-building exercises using the HGS Molecular Structure Model ...

Model-building exercises
using the HGS Molecular
Structure Model Kit: 3
Organic chemistry 2: sugars
and stereochemistry
Dr John Moody
1

Organic chemistry 2: sugars
and stereochemistry
In biochemistry the term sugar
refers to any of the simpler
carbohydrates. This includes the
sort of sugar that we might put in
our tea. Carbohydrates are organic
molecules containing carbon,
hydrogen and oxygen atoms (not to
be confused with hydrocarbons).
The aim of the model-building
exercises described here is to
introduce you to the structures of
some simple sugars that are of
importance in life, and at the same
time learn something about
stereochemistry, an important
concept in biochemistry. By building
the models you should also extend
your knowledge of functional
groups.
Exercise 1: aldehydes and
ketones
N.B. It is assumed that you have
already carried out the
Introduction to organic chemistry
exercises before starting on the
exercises described here.
First construct a model of propane
(CH 3 CH 2 CH 3 ). The diagram on the
right and the expanded chemical
formula should remind you of its
structure. You can check on the
2

tables on the laminated sheet to
make sure that you are using the
correct bond connectors.
Now replace two of the hydrogen
atoms on the first carbon with a
double bonded oxygen, i.e. form a
carbonyl group. Use a pair of
curved blue bond connectors to do
this.
You have just made an aldehyde
called propanal (CH 3 CH 2 CHO). Be
careful not to confuse this with
propanol, which is an alcohol.
Propanal is an aldehyde because it
contains an aldehyde group. Notice
that the term aldehyde is used here
to describe both the aldehyde group
and organic compounds containing
aldehyde groups.
Have a look at your model. Like the
carboxyl group, introduced in the
Introduction to organic chemistry
exercises, the aldehyde group is
also flat (planar).
Move the carbonyl group from the
first carbon to the second carbon.
You will have to move two hydrogen
atoms to the first carbon in
exchange.
You have now made an isomer of
propanal called propanone.
Propanone is an example of the
3

group of compounds called
ketones. Once again the term
ketone describes both the chemical
group and compounds which
contain ketone groups.
Propanone is more commonly
known by its trivial name, acetone.
Acetone is a volatile solvent. If you
have ever used nail-varnish
remover you will know what it
smells like! It is produced as a byproduct
of the metabolic changes
that occur in the human body during
starvation, in diabetes mellitus and
with a high fat diet. It may then be
possible to smell it on someone’s
breath.
4

Exercise 2: the simplest
sugars of all
To make a simple sugar, take your
model of acetone and replace one
of the hydrogen atoms on each of
carbons 1 and 3 with a hydroxyl
group. Use green bond connectors
for the C-O bonds.
The molecule you have just made a
model of has the trivial name
dihydroxyacetone. ‘di’ means two,
so this is acetone with two hydroxyl
groups. Its formal name is
1,3-dihydroxy propan-2-one.
Dihydroxyacetone can take part in
Maillard reactions. These are the
reactions that lead to the browning
of food during cooking (not the
blackening of food which is caused
by burning!). Dihydroxyacetone is
the active ingredient in many sunless
tanning agents, where it reacts
with proteins in the dead surface
layers of the skin.
(For a review on sunless tanning
see Fu et al. (2004) Journal of the
American Academy of Dermatology
50(5), 706-713.)
Dihydroxyacetone is one of two 3
carbon sugars, which are isomers
of each other. You can convert
dihydroacetone to the other 3
carbon sugar, glyceraldehyde, by
5

swapping the carbonyl group on
carbon 2 for the hydroxyl group and
a hydrogen atom from carbon 1.
You can tell that you are dealing
with isomers here because when
you converted one molecule to the
other you did not add or remove
any atoms or bonds.
Dihydroxyacetone is a ketone,
whereas glyceraldehyde, as its
name implies, is an aldehyde.
There are two broad classes of
simple sugars, those that are
ketones, which are called ketoses,
and those that are aldehydes, which
are called aldoses.
How do we define a simple sugar?
Simple sugars are a group of
molecules which usually have the
same generic molecular formula,
and which have similar properties.
They form an homologous series
(see Introduction to organic
chemistry). The generic chemical
formula for a simple sugar is
(CH 2 O) n , where n is greater than or
equal to 3.
Have a look at your model of
glyceraldehyde. Does it conform to
the formula (CH 2 O) n ?
In the representation of
glyceraldehyde shown a couple of
6

pages back the C-O bond on
carbon 2 was shown with a
‘squiggle’; you may have wondered
why. It is shown this way because
glyceraldehyde can have two
different stereoisomers in which
the configuration of the bonds on
carbon 2 are different. On the
diagram on the right a wedgeshaped
bond indicates that it is
projecting out of the plane of the
page.
Make a second molecule of
glyceraldehye.
Is it exactly the same as your first?
If it is, then what would you need to
do to make it different? If it is not,
then what is different about it?
You should be able to produce two
models that are mirror images of
each other. It is important to note
that these cannot be superimposed
one on the other.
Stereoisomers are defined as
molecules with the same atoms and
bonds, but where the arrangement
(configuration) of the bonds in
space is different.
Look at carbon 2 in either of your
models. This carbon has four
different chemical groups or
7

atoms connected to it, unlike
carbon 3 where two (hydrogen
atoms) are the same.
Any carbon atom like carbon 2 in
glyceraldehyde can have two
different configurations. These are
called the ‘left-handed’ or ‘laevo’
(from the Latin, laevus, meaning
left) and the ‘right-handed’ or
‘dextro’ (from the Latin, dexter,
meaning right) configurations.
Carbon 2 in glyceraldehyde is
referred to as a an asymmetric
carbon or chiral centre (from the
Greek, kheir, meaning hand).
Does this really matter? In physical
and chemical terms the answer is
‘not very much’. Both stereoisomers
of glyceraldehyde have the same
physical and chemical properties,
except for their interaction with
plane polarised light, which they
rotate in opposite directions.
However, when it comes to
biochemistry the difference matters
a great deal.
The left-handed form of
glyceraldehyde is indicated by
writing L-glyceraldehyde, while the
right-handed form is indicated by
writing D-glyceraldehyde, but how
do we know which is which?
8

There are rules for the naming of
stereoisomers, which we are not
going to go into in detail here.
However, if we know how to tell D-
and L-glyceraldehyde apart we can
use this to help us with other simple
sugars. This is made easier if we
use Fischer projections.
*
9

Take one your models of
glyceraldehyde and place it on a
piece of white paper with carbon 1
(the one in the aldehyde group) at
the top, and with the horizontal
bonds projecting out from the
paper. Conversely the vertical
bonds must project in towards the
paper.
Now look down from above and
draw a diagram showing carbon 2
and the four bonds coming of it. It
should look something like a plus
sign. Label each of the arms of your
+ with the formula for the chemical
group on that arm, e.g. H, if it is just
a hydrogen atom, or CHO for the
aldehyde group.
Follow the same procedure for your
other model, and when you have
finished put your two drawings side
by side. How do they compare?
Hopefully they look like the
diagrams shown below.
10

Glyceraldehyde is used as a
configurational standard for other
simple sugars. The Fischer
projections make it clear that the
two stereoisomers of glyceraldehyde
are mirror images of each
other. Pairs of stereoisomers that
are mirror images of each other are
called enantiomers.
Exercise 3: ribose and other
pentoses
The two stereoisomers of
glyceraldehyde, and dihydroxyacetone
are the only examples of
three carbon (3C) sugars (trioses).
As the number of carbons increases
the range of possibilities increases
because the number of chiral
carbons increases. With 5C sugars
(pentoses) there are two structural
isomers (aldopentose and ketopentose)
and a total of 12
stereoisomers!
The 5C sugar D-ribose is an
important cellular component. For
example, it forms part of the
structure of ribonucleic acids. The
structure of a transfer RNA, tRNA,
is shown on the right. D-ribose is
one of 8 different stereoisomeric
aldopentoses. The aim of this
exercise is to first build a model of
D-ribose, and then, using this
11

model, to explore the relationships
between the different stereoisomers
of D-ribose.
Take your model of D-glyceraldehyde
and lengthen it by adding
two hydroxymethylene groups
between carbons 1 and 2 (taking
carbon 1 to the one in the aldehyde
group).
You should now have a model of an
aldopentose: ‘aldo’ meaning there is
an aldehyde group at one end;
‘pent’ meaning that there are 5
carbons; and ‘ose’ indicating that it
is a sugar. Every carbon except the
one involved in the aldehyde group
should have a hydroxyl group
attached to it.
It may be an aldopentose, but is it
the one we set out to make,
D-ribose? Well one thing is for sure
at this stage, if you have followed
the instructions. The model you
have made must be of a
D-aldopentose. Why? If you draw a
Fischer projection of your model
you should be able to see why.
Follow the instructions below
carefully; it is quite easy to go
wrong!
First arrange the model so
that the carbon skeleton lies as a
12

linear zigzag, with the aldehyde
group facing away from you.
Take each of the four chiral
carbons in turn – start with
carbon 4.
Place the model on a piece
of white paper so that the
horizontal bonds on carbon 4
project away from the paper.
Look down on the model
from above and make a diagram
similar to those you made for D- and
L-glyceraldehyde.
Do the same thing with the
next chiral carbon (carbon 3). This
will entail turning the model over
so that the horizontal bonds on
the chiral carbon project away
from the paper.
Finally do the same thing the
last chiral carbon (carbon 2).
A Fischer projection of D-ribose is
shown to the right. How does yours
compare to this? You can tell if your
model is a D-aldopentose if the
configuration of the chiral carbon
(carbon 4) furthest away from
aldehyde group matches that of
D-glyceraldehdye. Remember that
glyceraldehyde is used as a
configurational standard for other
simple sugars. We can tell whether
13
D-ribose

a simple sugar is the D- or the L-
isomer by comparing its Fischer
projection with those of D- and L-
glyceraldehyde.
What about the rest of your model;
how does it compare with D-ribose?
There are three chiral carbons in
D-ribose and there are two possible
configurations of the bonds round
each of these giving 2 3 (i.e. eight)
different permutations. If necessary
adjust the configuration of carbons
2 and 3 so that they match those of
D-ribose (i.e. swap the hydroxyl
groups for the hydrogen atoms).
Now that you have got a model of
D-ribose, you can have a go at
converting it to some of the other
aldopentoses. First change the
configuration of carbon 2 (swap the
hydroxyl for the hydrogen). You
have converted from D-ribose to
D-arabinose. D-arabinose is not the
mirror image of D-ribose, so it is not
its enantiomer.
Where you have two sugars that
differ only in the configuration round
one carbon atom they are referred
to as epimers. A more general
term, diastereoisomers, is also
used to describe stereoisomers that
are not enantiomers, i.e. not mirror
images of each other.
D-arabinose
14

D-arabinose is not common in
nature. L-arabinose is much more
common. It is found in plant cell
walls and is a component of the
plant-derived gelling agent, pectin,
which is often used in jam.
Swap the configuration around
carbon 4. You now have L-xylose.
L-xylose is not found in nature, but
D-xylose is a common component
of plant cell walls. It is also used to
test for malabsorption problems in
the small intestine. The levels of
D-xylose in blood and urine are
measured before and after drinking
a solution of D-xylose.
If you swap the configuration of the
last chiral carbon, number 3, you
will make L-ribose, the mirror
image of D-ribose, i.e. its
enantiomer.
Finally, if you swap the
configuration of carbon 4 back
again you will make D-lyxose,
which is not found in nature.
So far in this exercise you have only
made aldopentoses, aldoses with
five carbons, but remember that
there are also ketopentoses, i.e.
five carbon sugars with a ketone
group rather than an aldehyde
group.
L-xylose
L-ribose
15

Take your model of D-lyxose and
swap the double-bonded oxygen
from carbon 1 with the hydroxyl
group and hydrogen atom from
carbon 2.
You now have a model of a
ketopentose. This one is called
D-xylulose. Ketopentoses are
named by inserting ‘ul’ into the
name of the most closely related
aldopentose.
In humans a genetic deficiency in
the L-xylulose reductase leads to
the appearance of high
concentrations of L-xylulose, the
enantiomer of D-xylulose in the
urine, a condition known as
pentosuria (from ‘pentose’,
meaning ‘five carbon sugar’, and
‘uria’ meaning ‘in the urine’).
Have a look at your model. How
many chiral carbons are there?
How many different stereoisomeric
ketopentoses must there be?
D-lyxose
D-xylulose
What would you have to do to
convert it to D-xylulose?
16

Exercise 4: glucose and
fructose
In animals D-glucose is an
important circulating metabolic fuel.
Nervous tissue, for example, is
normally completely reliant on it.
There is at least some truth in the
old advertising slogan ‘a Mars a day
helps you work, rest and play’.
D-glucose is one of twelve 6C
sugars, and each of these has a D-
and an L- form making 24
altogether. In nature it is mostly the
D-forms that are found. D-glucose is
an aldose or more specifically an
aldohexose.
Construct a model of D-glucose
using the Fischer projection to the
right as a guide. Make sure that the
configuration of each of the four
chiral (asymmetric) carbons is
correct. As before, focus on each of
the four chiral carbons in turn, and,
when drawing the Fischer projection
for that particular carbon, ensure
that that the horizontal bonds
project away from the page. It
may be useful at this stage to label
carbon 1 and carbon 5; there are
some labels in the box that you can
use.
The model that you have made has
an essentially linear carbon
17

skeleton. However, in a solution in
water most of the D-glucose would
be present in a cyclic form. When
an aldehyde or a ketone reacts with
an alcohol new chemical groups are
formed, called a hemiacetal and a
hemiketal, respectively. Since
simple sugars are both aldehydes
(or ketones) and alcohols (they
contain two or more hydroxyl
groups) at the same time, many can
react with themselves to form cyclic
hemiacetals (or hemiketals).
There are two types of cyclic (ring)
forms found in simple sugars: 5
membered rings (furanoses) and 6
membered rings (pyranoses).
Glucose can form both of these, but
is more likely to be found in a
pyranose form.
Make a pyranose form of D-glucose
by first swinging the oxygen of the
hydroxyl group on carbon 5
round towards the aldehyde
carbon (carbon 1) in your model.
The oxygen in the hydroxyl group
has a slight excess of electrons
(because of the electronegativity of
oxygen: see Introduction to
chemical bonding).
hemiacetal
group
18

It is able to donate a pair of
electrons towards carbon 1 (which
has a slight deficit of electrons
because of its double bond with an
oxygen atom. This starts off a set of
electron movements (bond
breakage and formation) which is
represented in the diagram below.
This sort of electron redistribution
is what we mean when we talk
about a chemical reaction.
The little red arrows in the diagram
represent movements of pairs of
electrons.
Try doing the rearrangements
shown in the diagram with your
model. You should end up with a
ring containing 5 carbon atoms and
1 oxygen atom. You can replace the
green bond connectors representing
C-O bonds in the ring with white
connectors because this better
represents the lengths of these
particular C-O bonds.
19

Look at your model from the side
with the oxygen atom in the ring
facing away from you and to the
right, with carbon 1 to the right, and
with carbon 6 sticking up. (It may
take you a while to work out which
is carbon 1 if you did not label it
earlier!) You should hopefully be
able to arange it to look something
like the diagram.
There may well be some
differences, however, in the
configuration of the molecule, or in
its conformation, or in both its
configuration and conformation.
Look at carbon 1. This is the one
that was part of the aldehyde group.
There are now four different
substituents on this carbon, so it is
now asymmetric; in the formation of
the ring it has become a chiral
carbon. There are, therefore, two
possible configurations of the bonds
round this carbon.
These are called the (alpha) and
(beta) anomers, and the chiral
carbon created when the ring forms
is called the anomeric carbon. The
perspective views that are often
used to represent these are called
Haworth projections.
20

The diagrams on the previous page
show a conformation called a
‘chair’ form, because of its vague
resemblance to chair. An alternative
conformation is a ‘boat’ form,
again because of its vague
resemblance to a boat!
Carefully rotate the C-C and C-O
bonds in the ring in order to switch
the conformation of your model
between chair and boat forms.
In a solution of D-glucose, at any
one time, less than 1% of the
molecules are in the open chain
form. Most of the molecules are in
the 6-membered (pyranose) ring
form with about 2/3 having the
configuration and about 1/3 the
configuration. A tiny amount of
the 5-membered (furanose) ring
forms would also be present.
Try making a furanose form of
D-glucose with your model. How
about 4-membered or 7-membered
rings – are these possible? Be
careful not to break any bond
connectors trying to make them!
Remake the pyranose form of
D-glucose. From its structure, and
what you learned in the
Introduction to chemical
bonding, do you think it would be
soluble in water?
21

Exercise 5: disaccharides
Does any of this matter? When you
are dealing with just simple sugars
in solution the answer is ‘not a lot’.
However, if we start assembling
sugars together to form larger
structures, like those found in living
organisms, it becomes very
important indeed, as hopefully you
will see.
Simple sugars like D-ribose and
D-glucose are called monosaccharides
(‘mono’ meaning one).
If two monosaccharides are joined
together we have a disaccharide
(‘di’ meaning two). Several
monosaccharides joined together
are called oligosaccharides (‘oligo’
meaning few), while many monosaccharides
joined together are
called polysaccharides (‘poly’
meaning much).
Table sugar or sucrose is an
example of a disaccharide, as is
milk sugar or lactose.
The aim of this exercise is to
explore the ways in which simple
sugars can link together, and the
possible consequences of this for
the properties of polysaccharides.
22

Make two models of D-glucose in its
6-membered ring form, each with
the anomeric carbon in the
configuration (-D-glucopyranose).
The disaccharide cellobiose, which
is a breakdown product of the plant
cell wall polysaccharide, cellulose,
consists of two glucose units
(residues) linked together.
Carbon 1 in one molecule is linked
via an oxygen atom to carbon 4 of
the other. Since the D-glucose is in
its configuration such a linkage is
called a (14) bond. Bonds like
this between sugar residues are
called glycosidic links. They are
formed in a reaction in which a
molecule of water is produced.
Such reactions are called
dehydration (or more generally,
condensation) reactions.
Join your two D-glucose molecules
together using the diagram below
as a guide.
23

Note, that in the diagram of
cellobiose on the last page bonds
shown with wedge shapes are
directed out of the plane of the page
whereas bonds shown with dashed
lines are directed into the plane of
the page.
Have a look at your model of
cellobiose. One of the glucose
residues is now locked in the ring
form (the one where carbon 1 is
involved in the glycosidic link).
However, the other can still open up
into the open chain form. The
aldehyde group in this glucose
residue can reform, and potentially
take part in chemical reactions,
whereas with the other residue this
cannot happen.
Sucrose consists of a glucose
residue and a fructose residue
joined together by an (12)
linkage. Recall that fructose is a
ketose, and that it is carbon 2 that is
part of the ketone group in ketoses,
i.e. it is carbon 2 that is the
anomeric carbon in ketoses. In
this case the glycosidic link locks
both residues into their ring forms.
24

Cellulose is a polysaccharide
consisting of many glucose
residues connected together in the
same way as that found in
cellobiose.
Amylose (a component of starch)
is also a polysaccharide consisting
of many glucose residues
connected together, but whereas
cellulose has great tensile strength,
and so is suitable as a structural
material for plant cell walls, amylose
has no tensile strength and is used
a storage material (for storing the
metabolic fuel glucose).
In both cases the glucose residues
are mostly held together by 14
links, so why are their properties so
different? The answer lies in the
detail of the glycosidic links. In
cellulose they are (14) links, but
in amylose they are (14) links.
Why should this make a difference?
25

Take your model of cellobiose; this
represents a small section of the
structure of cellulose. Make sure
that both glucose residues are in
the chair conformation. Then turn
second glucose residue (via rotation
round the glycosidic link) until it is
oriented 180° relative to the first
residue. Once you have done this
hold your model so that it
corresponds to the diagram below.
Once you have your model in this
position you should be able to form
a pair of hydrogen bonds (see
Introduction to chemical
bonding) between the two glucose
residues, as shown in the diagram.
It would be a good idea to use the
yellow bond connectors to make
these bonds so that you do not lose
track of which are hydrogen bonds.
What effect does the formation of
these hydrogen bonds have on your
model?
26

In amylose, where the glucose
residues are joined by (14)
linkages there is no strong
hydrogen bonding between
adjacent glucose residues. As a
consequence the structure is less
rigid.
27

Glossary of terms
Acetone
The simplest possible ketone. Its
systematic name is propanone.
Aldehye
An organic compound with a
terminal carbonyl group. The term
aldehyde group is also applied to
the terminal carbonyl itself.
Aldopentose
A pentose (5C sugar) with an
aldehyde group.
Amylose
A linear polymer of glucose found in
plants. Together with amylopectin,
which is a branched polymer of
glucose, amylose is a major
component of starch.
Anomer
A type of stereoisomer generated in
the cyclisation of simple sugars. In
their ring forms simple sugars have
a new chiral carbon, and there are
two possible configurations of
bonds round this. Anomers could
also be described as epimers or
diastereoisomers.
Asymmetric carbon
An asymmetric carbon has four
different chemical groups attached
to it. As a result it becomes chiral.
28

Cellobiose
A disaccharide consisting of two
D-glucose molecules linked by a
(14) glycosidic linkage.
Cellulose
A structural polymer of glucose,
containing predominantly (14)
linkages.
Chiral
A molecule or component of a
molecule is said to be chiral if it
cannot superimpose on its mirror
image.
Condensation
A chemical reaction in which two
molecules combine with the loss of
a small molecule. If the small
molecule is water then this is
referred to as a dehydration
reaction.
Dehydration
A specific type of condensation
reaction in which a molecule of
water is eliminated.
Diastereoisomer
Any stereoisomer that is not an
enantiomer.
Disaccharide
Two simple sugars (monosaccharides)
linked by a glycosidic
linkage.
29

Enantiomer
A stereoisomer that is the mirror
image of another stereoisomer.
Epimer
A stereoisomer that differs from
another stereoisomer in the
configuration of one chiral carbon.
Fischer projection
A 2D representation of a 3D
molecule obtained by projection
onto a surface.
Furanose
This is used to describe cyclic forms
of simple sugars with 5-membered
rings.
Glyceraldehyde
A triose monosaccharide (3 carbon
sugar) that is the simplest of all the
aldoses.
Haworth projection (perspective)
A perspective view used to
represent different stereoisomers of
simple sugars.
Hexose
A 6C simple sugar (monosaccharide).
Ketone
An organic compound containing a
carbonyl group linked to two other
carbon atoms, i.e. not a terminal
carbonyl. The term ketone group is
also applied to the carbonyl itself.
30

Ketopentose
A pentose (5C sugar) with a ketone
group.
Lactose
A disaccharide consisting of
-D-galactose and -D-glucose
linked by a (14) glycosidic
linkage
Monosaccharide
A simple sugar.
Oligosaccharide
Several simple sugars (monosaccharides)
linked by glycosidic
linkages.
Pentose
A 5C simple sugar (monosaccharide).
Pentosuria
An in-born error of metabolism
which results in high levels of the
pentose xylulose in the urine. It is
caused by a lack or deficiency in
the enzyme L-xylulose reductase.
Polymer
Large molecules make up of many
repeating units called monomers. In
biological molecules the monomeric
units once incorporated into the
polymer as often referred to as
residues.
31

Polysaccharide
Many simple sugars (monosaccharides)
linked by glycosidic
linkages.
Pyranose
This is used to describe cyclic forms
of simple sugars with 6-membered
rings.
Residues
This is used to describe repeating
units in a polymer after their
incoproration into the polymer.
(Configurational) stereoisomer
An isomer that contains the same
atoms and connections between
them as another molecule, but with
a different arrangement of these
bonds in space.
Sucrose
A disaccharide consisting of
-D-glucose in a pyranose ring and
-D-fructose in a furanose ring,
linked by a (12) glycosidic
linkage.
Triose
A three carbon simple sugar
(monosaccharide). There are only
two: glyceraldehyde and
dihydroxyacetone.
32

For illustrations labelled * the
following applies.
Permission is granted to copy,
distribute and/or modify this
document under the terms of the
GNU Free Documentation License,
Version 1.2 or any later version
published by the Free Software
Foundation; with no Invariant
Sections, no Front-Cover Texts,
and no Back-Cover Texts.
33