Introduction to Molecular Modeling
Consider the two molecules, A and B. Are they the same or different molecules?
What are the bond angles between the two chlorine atoms in molecule A? What are the
bond angles between the two chlorine atoms in molecule B?
H
Cl
Cl
H
H
H
Cl
Cl
A
B
At first glance, the answer may not be obvious. Indeed, the two molecules are 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 lose sight of the
fact 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 calculations.
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.
Quick Tip: Double clicking on the Select Tool icon is the same as selecting Add H &
Model Build.
23
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, Green. Any atoms or bonds you select will
now be highlighted green.
To determine the length of any bond, click on the bond you want to measure using the
Select Tool. 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. 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
molecule is. This will be useful when comparing the relative stabilities of different
molecules. Note that it is only useful to compare energies of molecules (or groups of
molecules) with the same total molecular formula.
24
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
carbon atoms are superimposed. Choose the Rotate in Plane Tool and right click and
drag on any of the three highlighted hydrogen atoms. 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.
25
Measure the C-C-H and H-C-H bond angles. Measure the distances 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.
H
HH
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
H
H
Ha H
H
H
H
H
H
Ha
Ha
H
H
Ha
Ha
H
H
H
H
H
Ha
H
26
Clear the drawing window and build a model of propane. Optimize and record its
energy. Using the Rotate out of Plane Tool, superimpose carbon atoms 1 and 2. This is
staggered propane. Again, if you were to rotate one of the carbon atoms 60° while
holding the other stationary you would generate eclipsed propane. Convert the staggered
propane to eclipsed propane as you did for ethane. Optimize and note its energy. Draw
the Newman projection for each conformer of propane.
Build a model of butane. Optimize and record its energy. Superimpose carbon atoms 2
and 3. The two terminal methyl groups are 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 four different 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 its energy. For each conformer, measure the distance between
carbon atoms 1 and 4.
CH3
CH3
H
CH3
H
CH3
H
CH3
H
H
H
CH3
H
H
H
H
CH3 Plot
Based onH their energies,
list the four
from
most stable to least.
H
H H
H conformers of butane
CHH
3
a graph of relative energy versus the dihedral angle between carbon atoms 2 and 3.
syn-periplanar
gauche
anticlinal eclipsed
anti
The molecule butane demonstrates an important concept in chemistry; isomerism. There
are two structural isomers of butane.
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:
Structural (skeletal) isomers: compounds that differ in connectivity within the
hydrocarbon framework only.
27
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. 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.
Q.1. Butane has the molecular formula C4H10. There are only two ways that four
carbon atoms and ten hydrogen atoms can be connected together. These are shown
below in both the condensed and line-bond form:
CH3
CH2
CH2
CH3
butane
CH3
CH3 CH
CH3
2-methylpropane
Build a model for each isomer of butane and optimize it. Measure the C-C-C bond
angles. Measure the distance between hydrogen atoms on adjacent carbon atoms.
Q.2.
A.
Using a pencil and paper, draw all the structural isomers for C5H12.
B.
Look at the carbon atoms in the structures that you drew. Are they all the same?
You will notice that they differ by the number of attached hydrogen atoms. CH3 groups
are called methyl groups. CH2 groups are called methylene groups, and CH groups are
called methine groups. Additionally, we can also classify the carbon atoms as primary
(1°), secondary (2°), tertiary (3°), or quaternary (4°) depending on the number of carbon
atoms attached to it. Thus, a carbon atom attached to only one carbon atom is called a
primary carbon atom. A carbon atom attached to two other carbon atoms is called a
secondary carbon atom. A tertiary carbon atom is bonded to three other carbon atoms
28
and a quaternary carbon atom is bonded to four other carbon atoms. You should note that
these designations do not hold for multiply bonded carbon atoms.
For each isomer of C5H12, identify the methyl, methylene, and methine groups and label
each carbon as 1°, 2°, 3°, or 4°.
C.
Give the IUPAC name for each isomer of C5H12. One common mistake when
drawing isomers for a given molecular formula is to draw structures which look different
but in fact are the same. One way to avoid this is to name each isomer according to
IUPAC rules. Since isomers represent different molecules, each one will have a different
name (assuming it is named correctly!).
D.
Build a model for each isomer of C5H12. Optimize the structure. Record the C-CC bond angles and the distances between hydrogen atoms on adjacent carbon atoms.
Superimpose any two adjacent carbon atoms. Are the hydrogen atoms eclipsed or
staggered?
Q.3.
For the formula C4H8O, at least 25 different constitutional isomers can be drawn.
A.
Find and draw the following:
a) two different aldehydes.
b) one ketone.
c) four linear alcohols.
Name each of these isomers according to IUPAC nomenclature, and label each carbon
atom as 1°, 2°, 3° or 4°.
B.
Find and draw the following:
a) four different linear ethers.
b) three different cyclic ethers.
For each of these isomers, label each carbon atom as 1°, 2°, 3° or 4°.
C.
Of the isomers that you drew, build a model of one aldehyde, one ketone, one
alcohol and one ether. Optimize each structure and look at the functional group
from different angles. Is it flat? Bent? What is the spatial relationship of the
functional group with the rest of the molecule?
D.
Try and find all 25 (or more) different isomers.
29
Molecular Modeling II
In the previous lab, we looked at conformers of some small aliphatic hydrocarbons.
These different conformers exist because of the possibility of rotation about the carboncarbon bonds. The conformations of cyclic hydrocarbons are influenced differently than
their acyclic analogues because of the restriction of free rotation.
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?
Relatively speaking, would you expect cyclopropane to be a stable molecule?
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? Relatively speaking, would you expect
cyclobutane to be a stable molecule?
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?
Relatively speaking, which of these three cyclic hydrocarbons is more stable? Provide
two reasons for your answer.
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.
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cyclohexane
H
H
H
H
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
30
whether the hydrogen atoms are staggered or eclipsed. Relatively speaking, how does
cyclohexane compare in stability to cyclopropane, cyclobutane, and cyclopentane?
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
C5
H
H
H
H
C3
C4
C5
C1
C6
H
H
C6
H
=
H
H
C2
H
H
H
H
C4
H
H
C1
C2
C3
H
H
H
H
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 83) 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
He
Ha = axial hydrogen
He = equatorial hydrogen
He
Ha
Ha
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.
Ha
C
He
Ha
1
He
He
C
4
He
C4
C
Ha
Ha
31
1
Another important conformer of cyclohexane is the boat
H
H
conformer. The boat conformer has a higher energy then the
H
H
chair conformer. Prove this by building a model of the boat H
H
H
conformer of cyclohexane. To make the boat conformer you will
H
need to start with an optimized model of the chair conformer.
H
H
Highlight the four carbon atoms that make up the seat of the chair
H
H
(see Figure A below). In the Select menu, choose Name
Boat conformer
Selection and Plane. Deselect all atoms and then select one of
the two out-of-plane carbon atoms and its two hydrogen atoms. In the Edit menu, select
Reflect. This will reflect the chosen atoms atom about the defined plane (Figure 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
C
C
C
C
H
H
A. Four carbon ‘seat’.
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.
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 and one where the methyl group is in the equatorial position.
H
H
H
Me
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
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, are shown in
the chair conformation of methylcyclohexane.
32
In the corresponding Newman projection, which is looking down the C2-C1 and C4-C5
bonds, the gauche interaction between the C3-C2 bond and the axial methyl group is
highlighted. Draw the Newman projection looking along the C1-C6 and C3-C4 bonds.
Highlight the gauche interaction between the methyl axial group and the C5-C6 bond
H
C5
H
H
CH3
C3
C4
C3
H
H
C4
H
C2
CH3
H
C1
C6
H
H
H
H
C2
H
C6
H
H
H
H
When the methyl group is in the equatorial position, there are no gauche interactions. As
the Newman projection clearly shows, the methyl group is anti to the C2-C3 and C5-C6
bonds. The anti arrangement places the methyl group as far away as possible from the
neighbouring carbon atoms.
H
C5
H
H
H
H
H
C3
C4
C1
C6
C2
H
H
H
H
H
C3
H
C4
CH3
C2
H
C6
CH3
H
H
H
Another factor to consider are the 1,3-diaxial interactions. When the methyl group in
methylcyclohexane is in the axial position, there is a steric interaction between it the
hydrogen atoms attached to carbon atoms 3 and 5. When the methyl group is in the
equatorial position, it is pointing away from the ring and these steric interactions are
absent.
H
H
H
H
H
C5
H
C3
C4
H
H
H
C3
C4
H
H
H
C2
C5
H
C1
C6
H
H
H
H
H
C2
H
H
C1
C6
H
H
H
H
Equatorial methyl group. No
1,3-diaxial interactions
Axial methyl group. 1,3-diaxial
interactions
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 in the equatorial position.
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
33
H
H
H
CH3
Convince yourself that the conformer with the methyl group in the equatorial position is
more stable. Build optimized models of both conformers and calculate their energies.
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.
CH3
H3C
H
CH3
H
H
H
H
H
H
CH3
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
CH3
H
H
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
A
H
CH3
H
CH3
H
H
B
CH3
CH3
H
H
H
CH3
H
H
H
H
H
H
H
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
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
34
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 (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.
35