Introduction to Molecular Modeling
As the title implies, the following ‘dry’ lab is meant to be an introduction to the exciting
(OK, maybe not exciting but definitely important) world of molecular modeling. Why,
you might ask, is molecular modeling important? Let me answer that question (as I
usually do) with another question. Look at molecules A and B. Are they the same or
different? What do you think the bond angle is between the two chlorine atoms in
molecule A? What about molecule B?
H
Cl
Cl
H
H
H
Cl
Cl
B
A
At first glance, the answer may not be obvious. The two molecules are in fact the same
and the bond angles between the two chlorine atoms are identical at 109.5°. This
example drives home an important aspect of organic chemistry: the importance of the 3dimensional structure of organic molecules. As organic chemists, we often draw
structures and reactions on paper. Although this is useful, we must never forget that
molecules are 3-dimensional structures. For this reason, it is strongly recommended that
a modeling kit be used when studying organic chemistry. Fortunately, chemists also have
modeling programs at their disposal.
In addition to viewing structures three
dimensionally, modeling programs allow us to measure bond lengths, bond angles, and
calculate energies. The program you will be using for this lab is called Hyperchem®.
One of the purposes of this lab is to familiarize you with the basics of Hyperchem® by
building some models and performing some basic calculations.
Before we start I have to apologize. What follows in an instructional ‘how to’ and
there are very few ways to make ‘how to’ instructions more exciting than watching paint
dry. For that I’m sorry. I do not, however, feel bad enough to let you not do this lab.
Acyclic Aliphatic Hydrocarbons
Start the HyperChem program by selecting Start, Programs, Class Software,
HyperChem Std 5.1. It is easier to work on a white background. To change the
background colour select File, Preferences, Window Color, White, OK. The main tools
you will be using are shown below:
Draw
Select
Rotate in Plane
Rotate out of Plane
Start by drawing the molecule methane (CH4). To draw a carbon atom, double click on
the Draw Tool. A periodic table will appear. Select the element carbon and close the
periodic table window. Now click anywhere on the drawing surface and a carbon atom
will be seen. To add the hydrogen atoms, click on Build, Add H & Model Build.
11
Quick Tip: Double clicking on the Select Tool icon is the same as selecting Add H &
Model Build provided that Explicit Hydrogens in the Build menu is not checked
Note that when you are building molecules in HyperChem®, you need only draw the
carbon skeleton. The program will add the requisite number of hydrogen atoms when
you click the Add H & Model Build command. To obtain a different type of model,
select Display, Rendering, Balls and Cylinders, OK. To vary the size of the balls select
Display, Rendering, Balls and vary the Ball Radius slider. Use the Rotate in Plane and
Rotate out of Plane Tools to view your molecule at different angles and positions. To
use the Rotate tools, click anywhere in the main drawing window while dragging the
mouse. Before proceeding, you will need to change the ‘highlight’ colour. In the File
menu, select Preferences, Selection Colour, ‘Choose a colour’. Any atoms or bonds
you select will now be highlighted in the chosen colour.
To determine the length of any bond, click on the bond you want to measure using the
Select Tool. This will highlight both of the atoms attached to this bond. The value, in
Angstroms (Å), will appear in the information bar at the bottom left of the screen. For
the molecule methane, each C-H bond distance will be 1.09Å. You can also measure the
distance between any two atoms using the same procedure. When selecting atoms, make
sure that you click on the centre of the atom. It is important to realize that these are
unoptimized values. Later we will show how to obtain an optimized value. In order to
determine a bond angle, first make sure that the Multiple Selections option in the Select
menu is selected and then use the Select Tool and click on two bonds (three atoms should
be highlighted). The bond angle will appear in the information bar at the bottom left of
the screen. For the molecule methane, each H-C-H bond angle will be 109.471°.
Quick Tip: If you left click on the background with the Select Tool the entire molecule
will be selected. If you right click on the background with the Select Tool,
everything will be deselected. If you accidentally select the wrong bond or
atom, deselect it by right clicking on it.
HyperChem® has the ability to optimize molecules. When we optimize a molecule we
are calculating the most stable structure of the molecule. There are many different levels
of calculations; some more advanced than others. For our purposes we will use basic
method of calculations since the molecules we are investigating are small. In the Setup
menu, select Semi-empirical, then AM1. To optimize a structure, select Geometry
Optimization in the Compute menu.
NOTE: BEFORE STARTING THE GEOMETRY OPTIMIZATION, YOU MUST
MAKE SURE THAT EVERYTHING IS DESELECTED IN THE
DRAWING WINDOW.
Optimize the structure of methane as described above. When the geometry optimization
calculation is done, the energy of the molecule will be displayed in the information bar.
The energy for methane is -388.1 kcals. Note that the energy is in kilocalories (kcals)
and that the value is negative. The more negative the energy, the more stable the
12
molecule is. This will be useful when comparing the relative stabilities of different
isomers. Note that it is only useful to compare energies of molecules (or groups of
molecules) with the same total molecular formula.
Let us now look at molecules A and B more closely. To draw molecule A, or
dichloromethane, you will need to change two of the hydrogen atoms of methane to
chlorine atoms. Double click on the Draw Tool to bring up the periodic table. Select the
element chlorine and then convert two hydrogen atoms into chlorine atoms by clicking
them. Two chlorine atoms will be appear larger then the two hydrogen atoms. To make
the atoms different colours, select Element Colour, in the Display menu. Here you can
give each element a different colour. Do not select the colour green as this is the
‘highlight’ colour. You should now have a carbon atom which is bonded to two
hydrogen and two chlorine atoms. Optimize the molecule as described above and note its
energy. Measure and record the values of the bond lengths of the C-H and C-Cl bonds.
Measure and record the values of the Cl-C-Cl, Cl-C-H, and H-C-H bond angles. Use the
Rotate in Plane and Rotate out of Plane Tools to generate the view depicted in
molecule A. Now rotate the molecule to generate the view depicted in molecule B.
Hopefully you are now convinced that both structures A and B represent the same
molecule.
Quick Tip: To delete everything in the drawing window, you can either select
everything by left clicking on the background with the Select Tool and then
pressing the Delete key or you can right click on the atoms with the Draw
Tool.
Clear the drawing window and draw a molecule of ethane. Using the Draw Tool (make
sure that the element carbon is selected in the periodic table) click in the drawing window
to add a carbon atom then click on this carbon atom and drag away. This will add
another carbon atom bonded to the first one. Add the hydrogen atoms by selecting Add
H & Model Build. The program will automatically generate ethane in the staggered
conformation. Optimize this structure and note its energy. Measure the C-C-H and H-CH bond angles. Measure the distances between the hydrogen atoms on adjacent carbon
atoms.
H
H
H
H
H
H
H
H
H
H
H
Staggered
H
Eclipsed
To make ethane in the eclipsed conformation, you must first make sure that Multiple
Selections is on in the Select menu. Make sure that molecule is in an orientation where
you can clearly see all the atoms. Using the Select Tool, highlight all four atoms of one
methyl group. Using the Rotate out of Plane Tool, position the molecule so that both
13
carbon atoms are superimposed. Next, choose the Rotate in Plane Tool and right click
and drag anywhere on the background. The methyl group that you highlighted will now
rotate along the carbon-carbon bond. Position the hydrogen atoms so that they are
eclipsed. Optimize this structure and record its energy. Measure the C-C-H and H-C-H
bond angles. Measure the distance between the hydrogen atoms on adjacent carbon
atoms. Which conformer is more stable? Why?
Newman projections are often used to show conformational relationships between certain
atoms. Newman projections are drawn by looking down the axis of a carbon-carbon
bond. Ethane has only one carbon-carbon bond so the Newman projection is drawn
looking down this bond. Shown below is the Newman projection for the two conformers
of ethane. The front carbon atom is represented as the point where the three lines
intersect. The second carbon atom is represented as the circle. The Newman projections
of staggered and eclipsed ethane clearly show the spacial relationship of the hydrogen
atoms. It is important that you learn to read and draw Newman projections.
HH
H
H
H
H
H
H
H
H
H
H
staggered ethane
eclipsed ethane
Another useful way to look at the conformational relationships of molecules is to plot the
energy of each conformer versus the angle of rotation of one carbon atom relative to the
other. This is demonstrated below with ethane. Start with the higher energy eclipsed
conformer. Rotation of a methyl group by 60° will generate the lower energy staggered
conformation. Rotation by another 60° will regenerate an eclipsed conformer. Repeating
this through 360° will alternately generate the eclipsed and staggered conformers giving a
sinusoidal wave.
Ha Ha
Ha H
H
H
H
H
H
H
H
Ha
Ha
Ha
H
H
Ha
H
H
H
H
H
H
Ha
14
Clear the drawing window and build a model of propane. Optimize and record its
energy. This is ‘fully’ staggered propane. Using the Rotate out of Plane Tool, look
down the two carbon-carbon bonds. You will notice that all of the hydrogen atoms are
staggered. As you did with ethane, rotate one of the carbon atoms 60° while holding the
others stationary. This will generate a propane molecule with one staggered carboncarbon bond and one eclipsed carbon-carbon bond. Optimize and note its energy.
Finally, make ‘fully’ eclipsed propane by rotating the other carbon-carbon bond 60°.
Optimize and note its energy. Which of the three propane conformers is the most stable?
Which is the least? Is the stability as you expected?
Build a model of butane. Optimize and record its energy. Superimpose carbon atoms 2
and 3. The two terminal methyl groups will be as far apart as possible. Measure the
distance between carbon atom 1 and carbon atom 4. This is called the anti conformer of
butane. Rotation of carbon 3 by 60° increments will generate six conformers. These are
shown below as Newman projections. Note that there are two equivalent gauche and
anticlinal eclipsed conformers. Starting with the anti conformer of butane, generate each
conformer and calculate and note its energy. For each conformer, measure the distance
between carbon atoms 1 and 4.
CH3
CH3
H
H
H
CH3
H
H H
syn-periplanar
CH3
H
CH3
H
H
H
H
gauche
CH3
H
H
H
CHH
3
anticlinal eclipsed
H
CH3
anti
Based on their energies, list the four conformers of butane from most stable to least
stable. For all six conformers of butane, plot a graph of relative energy versus the
dihedral angle between carbon atoms 2 and 3 (similar to the graph shown on the previous
page for ethane).
When you first start looking at the structure of organic molecules, it is important to be
aware of isomers. Isomers are molecules that have the same molecular formula but
different structure. There are several different types of isomers: constitutional isomers,
geometric isomers, and stereoisomers. In today’s lab, we will only be looking at
constitutional isomers. Constitutional isomers are molecules that have the same
molecular formula but differ in connectivity. Consider the two molecules dimethyl
ether and ethanol:
CH3OCH3
CH3CH2OH
Both dimethyl ether and ethanol have a molecular formula of C2H6O but the arrangement
of the atoms is different. Constitutional isomers can be divided into several
subcategories. Although you should be aware of these different subcategories, it is more
important that you remember that they all represent constitutional isomers. The
subcategories are:
15
Structural (skeletal) isomers: compounds that differ in connectivity within the
hydrocarbon framework only.
Positional isomers: compounds in which the placement of the functional group is
different.
Functional isomers: compounds in which the different connectivity gives rise to
different functional groups.
In the above example, dimethyl ether and ethanol can be described as constitutional
isomers or, more precisely, as functional isomers. It is important to realize that isomers
represent different molecules and thus will have different properties. Some isomers have
very different physical properties (solid and a liquid) while others have the exact same
physical properties except for the direction in which they rotate plane polarized light.
You will look at these properties in more detail later.
Cyclic Aliphatic Hydrocarbons
In the first part of this lab, you looked at conformers of some small aliphatic
hydrocarbons. These different conformers exist because of the possibility of rotation
about the carbon-carbon bonds. The conformations of cyclic hydrocarbons are
influenced differently than their acyclic analogues because of the rotation about carboncarbon bonds are restricted.
Build a model of cyclopropane: Make a triangle of carbon atoms then select Add H &
Model Build to finish the structure. Optimize the molecule and record its energy.
Measure the C-C-C bond angles. Measure the distance between hydrogen atoms on
adjacent carbon atoms. Position the molecule so that any two carbon atoms are
superimposed. Are the hydrogen atoms on adjacent carbons atoms eclipsed or staggered?
Build a model of cyclobutane: Make a square of carbon atoms and then select Add H &
Model Build. Optimize the molecule and record its energy. Measure the C-C-C bond
angles and measure the distance between hydrogen atoms on adjacent carbon atoms.
Superimpose any two carbon atoms and note the spatial relationship between the
hydrogen atoms. Are they staggered or eclipsed?
As you did for cyclopropane and cyclobutane, build a model of cyclopentane. Optimize
the structure and record its energy. Measure the C-C-C bond angles and measure the
distance between hydrogen atoms on adjacent carbon atoms. When looking down a
carbon-carbon bond, are the hydrogen atoms eclipsed or staggered? Is cyclopentane flat?
Build a model for cyclohexane. Optimize the structure and record its energy. Using the
Rotate out of Plane tool, look at the molecule from different angles and positions. Is
cyclohexane flat? The cyclohexane molecule will be in what is called the ‘chair’
conformation.
16
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cyclohexane
H
H
Chair conformer
What are the C-C-C bond angles? Superimpose any two adjacent carbon atoms. Are the
hydrogen atoms staggered or eclipsed? Do this for every carbon-carbon bond, noting
whether the hydrogen atoms are staggered or eclipsed. Based on their calculated
energies, rank the four cyclic hydrocarbons that you just looked at from least to most
stable. Give one good reason why the most stable cyclic hydrocarbon is lower in energy
than the least stable one.
We can also draw Newman projections for cyclohexane rings. The Newman projection
shown below is drawn looking down both the C2-C1 and C4-C5 bonds. The Newman
projection clearly shows how the hydrogen atoms are staggered with respect to each
other. Also note that all the carbon-carbon bonds are gauche with respect to bonds
emanating from adjacent carbon atoms. For example, sighting down the C2-C1 bond a
gauche interaction can be seen between the C3-C2 bond and the C6-C1 bond. This
interaction is shown in the Newman projection with highlighted bonds.
H
H
H
H
C5
H
H
C3
C4
H
C5
C1
C6
=
H
H
C2
H
H
H
H
C6
H
C4
H
H
C3
H
C1
C2
H
H
Newman projection of
chair cyclohexane
H
chair cyclohexane
It is very important that you learn how to draw cyclohexane in the chair conformation.
Your textbook (Sorrell, 1st Ed. page 136; 2nd Ed. page 85) has an excellent description on
how to properly draw cyclohexane in its chair conformation. You will also notice that
there are two different types of atoms or bonds attached to a cyclohexane ring. They are
described as axial and equatorial. These are shown on the diagram below. Since studies
in organic and biological chemistry frequently encompass six-membered rings, mastery
of drawing chair cyclohexane rings with properly placed hydrogen atoms is essential to
understanding their energetics and reactivity. It would be wise to practice drawing
cyclohexane in the chair form until you can draw the ring with appropriately placed
hydrogen atoms without difficulty.
Ha
Ha
He
He
Ha
He
He
Ha = axial hydrogen
He = equatorial hydrogen
He
Ha
Ha
He
Ha
17
Although cyclohexane has restricted rotation about its carbon-carbon bonds, it is still a
flexible molecule. Cyclohexane undergoes rapid ring-flips in which one end moves
down and the other end moves up. As a consequence of this ring-flip, the axial atoms
become equatorial and the equatorial bonds become axial. This is illustrated below (for
clarity, only four of the twelve hydrogen atoms are shown).
Ha
C
He
Ha
1
He
He
C
4
He
C4
C
Ha
Ha
1
Another important conformer of cyclohexane is the boat conformer. The boat conformer
has a higher energy then the chair conformer. Prove this by building a model of the boat
conformer of cyclohexane. To make the boat conformer you will
H
H
need to start with an optimized model of the chair conformer.
H
Highlight the four carbon atoms that make up the seat of the chair H
H
H
(see Figure A). In the Select menu, choose Name Selection and
H
H
Plane. Deselect all atoms and then select one of the two out-ofH
H
plane methylene groups (CH2). In the Edit menu, select Reflect.
H
H
This will reflect the chosen atoms about the defined plane (Figure
Boat conformer
B). Optimize this structure and record its energy. Rotate the
molecule and look down each carbon-carbon bond. Are the hydrogen atoms staggered or
eclipsed? Provide one good reason why you think the boat conformer of cyclohexane is
higher in energy than the chair conformer.
H
H
H
C
C
H
C
C
H
H
Fig. A. Four carbon ‘seat’.
H
H
Fig. B. Reflection of the methylene
group about the defined plane.
The chair and boat form of cyclohexane are the two most common conformers. There are
other conformers but we will not be looking at these at this time. For more information
on these other conformers, refer to your textbook.
18
Let us now look at what happens when we substitute a hydrogen atom on cyclohexane for
some other group. Suppose we were to substitute a hydrogen atom for a methyl group.
This would give rise to two different chair conformers; one where the methyl group is in
the axial position (Figure C) and one where the methyl group is in the equatorial position
(Figure D).
H
H
H
Me
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Fig. C.
H
H
Fig. D.
What difference, if any, is there between the two structures? What is the relative stability
of these two molecules? The key to answering these questions is to look at the gauche
interactions between the methyl group and neighboring carbon atoms. For the conformer
with the axial methyl group, two gauche interactions, indicated by arrows (Figure E), are
shown in the chair conformation of methylcyclohexane. In the corresponding Newman
projection (Figure F), which is looking down the C2-C1 and C4-C5 bonds, one gauche
interaction between the C3-C2 bond and the axial methyl group is highlighted in bold. To
see the second gauche interaction, draw the Newman projection looking along the C1-C6
and C3-C4 bonds.
H
CH3
H
H
C5
H
H
C3
C4
CH3
H
C1
C6
C2
C3
H
C4
H
H
H
C2
C6
H
H
H
H
H
H
Fig. F.
Fig. E.
When the methyl group is in the equatorial position, there are no gauche interactions
(Figure G). As the Newman projection clearly shows, the methyl group is anti (180°) to
the C2-C3 bond. The anti arrangement places the methyl group as far away as possible
from the neighbouring carbon atoms (Figure H).
H
H
H
H
C5
H
H
C3
C4
H
C1
C6
H
C2
H
H
C3
C4
CH3
H
H
H
C2
C6
H
CH3
H
H
Fig. H.
Fig. G.
19
Another factor to consider are the 1,3-diaxial interactions. When the methyl group in
methylcyclohexane is in the axial position, there are steric interactions between it and the
hydrogen atoms attached to carbon atoms 3 and 5 (Figure I). When the methyl group is
in the equatorial position, it is pointing away from the ring and these steric interactions
are absent (Figure J).
H
H
H
H
H
H
C5
H
H
C3
C4
H
C5
H
C1
C6
C2
H
H
C3
C4
H
H
H
H
H
H
C2
H
H
C1
C6
H
H
H
H
Fig. J.
Fig. I.
Methylcyclohexane illustrates an important point. The most stable position for any group
on a cyclohexane ring larger than hydrogen is the equatorial position. Thus, although
methylcyclohexane exists as both conformers, the equilibrium lies further on the side
where the methyl group is in the equatorial position.
H
H
H
CH3
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Convince yourself that the conformer with the methyl group in the equatorial position is
more stable. Build optimized models of both conformers and calculate and record their
energies and their energy difference. For each optimized model, use the Rotate out of
Plane and Rotate in Plane tools to position the molecule like the Newman projections
depicted in Figures F and G respectively. You should be able to see one of the gauche
interactions. Rotate the molecule to generate the second Newman projection which
shows the other equivalent gauche interaction. Finally, for each conformer, change the
rendering to Overlapping Spheres. This gives a better idea as to how much space each
atom occupies. If you press the F2 key, you can toggle back and forth between the last
two renderings (Balls and Cylinders and Overlapping Spheres). In the Overlapping
Spheres rendering, you will see that when the methyl group is axial it is much closer to
the hydrogen atoms attached to carbon atoms 3 and 5 (1,3-diaxial interactions, Fig I) then
when it is equatorial (no 1,3-diaxial interactions, Fig J).
What happens if cyclohexane is substituted with a group larger than methyl? As the
group increases in size, the equilibrium will lie further and further to the side with the
group in the equatorial position. This is exemplified with tert-butylcyclohexane. The
tert-butyl group is so large that the equilibrium lies almost completely on the side of the
equatorial conformer.
20
CH3
H3C
CH3
H
H
H
H
H
H
H
CH3
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
CH3
H
H
Build optimized models for both conformers of tert-butylcylcohexane. When optimizing
the conformer with the tert-butyl group in the axial position, watch the tert-butyl group.
You should see the carbon-carbon bond that attaches it to the ring elongate as well as the
tert-butyl group itself move away from the top of the ring. Essentially, the molecule
undergoes a major distortion in order to accommodate the size of the substituent. Record
the energies of both conformers and calculate the energy difference. Is the difference
between the two tert-butylcyclohexane conformers bigger or smaller then the difference
between the two methylcyclohexane conformers? Why? Toggle between the Balls and
Cylinders and Overlapping Spheres renderings to get a better sense of the size of the
tert-butyl group relative to a methyl group.
So far, we have only looked at monosubstituted cyclohexane rings.
With
monosubstituted cyclohexane rings, we looked at the relationship of the substituent
between conformers. As we turn our attention to disubstituted cyclohexane rings, you
will see that not only do we need to look at the relationship between conformers, but we
also need to look at the relationship of the two substituents within a certain conformer.
This relationship is refered to as its configuration. Consider the three molecules (A, B,
and C) of 1,2-dimethylcyclohexane shown below.
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
H
B
CH3
H
H
H
CH3
H
H
H
H
H
H
H
CH3
A
H
H
H
H
H
C
What different is there between these structures? The first thing to look at is the
relationship between the two methyl groups. They are either both in the axial position,
both in the equatorial position, or one in the axial and one in the equatorial position. The
second thing to look at is the relationship of the substituents relative to a plane defined by
the six carbon atoms of the ring. The methyl substituents are either above or below this
plane. When two substituents are on the same side of the plane of the ring, they are said
to be in the cis configuration. When the two substituents are on opposite sides of the
ring, they are said to be in the trans configuration. Therefore, compound A is in the
trans configuration because one methyl group is above the plane of the ring and the other
methyl group is below it. When naming compounds, the cis/trans descriptor is placed in
front of the name and is italicized. The proper IUPAC name for compound A is thus
trans-1,2-dimethylcyclohexane. Look at compound B. Although the two methyl groups
21
are both in the equatorial position, they are still trans to each other. One methyl group is
above the plane of the ring and the other is below it. Therefore, compound B is also
trans-1,2-dimethylcyclohexane. Compound C, where both methyl groups are above the
plane of the ring, represents the cis configuration. The full IUPAC name for compound
C is cis-1,2-dimethylcyclohexane. Although we looked at three different molecules,
disubstituted cyclohexanes can only have two different configurations: cis or trans.
Build a model for each of the three dimethylcyclohexane molecules (A, B, and C) and
calculate their energies. Place them in order of increasing stability and provide a
rationale for this order.
Cis and trans isomers can also be drawn for 1,3-dimethylcyclohexane and 1,4dimethylcyclohexane. For each of these two molecules, draw the isomers and decide
which is most stable. Build models for each isomer and calculate their energies. Are the
relative stabilities what you expected? Provide a rationale for the order of their relative
stabilities.
22