Experiment Group CS
Computational Chemistry
Computational Chemistry can be used to predict the energies,
shapes, dipole moments and other properties of compounds.
Purpose:
Schedule
of the labs:
These experiments will introduce you to the techniques and limitations of
computational chemistry. You will use computational methods to calculate properties
of small molecules which can then be compared.
Concepts Lab
Experiment 1: Molecular Orbital Calculations



Use PC Spartan to obtain information about simple molecules.
Identify basic organic functional groups and interpret lines drawings.
Examine and compare characteristics of small molecules
Application Lab
Experiment 2: Synthesis and Purification of Aspirin and Comparison of its
Acidity to Salicylic Acid Using Molecular Orbital Calculations


Scenario:
Use molecular orbital calculations to find a physical property that correlates with
acidity
Synthesize and purify aspirin
The development of new medications is an expensive and time consuming
process. Scientists used to be limited to screening natural products or synthesizing new
compounds, and then conducting extensive testing of drug effectiveness. The
development of high speed computers and computer codes has significantly reduced the
time and labor involved in developing new drugs. Now, scientists can use calculations
to predict the shape and nature of a target site for drug interaction, and use calculations
to predict the properties of compounds that would interact with the target site. They can
CC-1
create virtual experiments that examine drug effectiveness and interactions. They can
eliminate those compounds that fail the virtual tests, and avoid the labor intensive
synthesis and testing of the real compounds. Computational chemistry has become a
very powerful technique, when properly applied.
Greeks and Romans have used aspirin-like preparation way back during ancient
times. They found that the extract from willow or poplar bark called salicigen can be
used as a pain reliever (analgesic). In the middle of the last century, it was found that
salicigen is composed of a molecule of salicylic acid and a sugar molecule. The use of
salicylic acid was not successful since it has two nasty side effects  a terrible taste and
gastric irritation.
Felix Hoffman, a chemist for Friedrich Bayer, a German dye company, got
interested in creating the modern version of aspirin when his father complained about
the side effects of salicylic acid. Hoffmann hypothesized that the acidic nature of
salicylic acid could be reduced by the addition of an acetyl group, OCCH3, in place of a
hydrogen on an OH group. (At that time molecular modeling programs did not exist.)
Hoffmann made the compound which we now know as aspirin and then Bayer tested it
on animals and human subjects (we refer to now as clinical trials) to test his hypothesis.
HO
O
HO
OH
O
CH3
O
O
Salicylic Acid
Aspirin
Today there are many powerful molecular modeling programs used in the drug
industry for designing new drugs.
As an intern at Pharm Tech, you are given the task by the CEO of Pharm Tech,
Marty Mann, to try out a relatively simple program called Spartan. He wants you to
find out if Spartan could have been used by Hoffman if it had been available during his
time to predict if aspirin would indeed be less acidic than salicylic acid. In your first
experiment, you will become familiar with Spartan, and in your second experiment, you
will use Spartan to characterize the properties of aspirin and salicylic acid.
CC-2
NAME:____________________
Experiment CC-1: Molecular Orbital Calculations
Pre-laboratory Assignment (due before lab begins)
(Palko 12-9-10)
Valence-Shell Electron-Pair Repulsion (VSEPR) theory allows us to qualitatively predict the most
probable structure and the polarity of a molecule. More quantitative methods, called molecular orbital
(MO) calculations, can also be used to make such predictions. In this pre-lab, you will use VSEPR to
predict shapes of simple molecules on which you will perform more accurate MO calculations next
week. Your General Chemistry text can help you predict shapes and bond angles – look under
“Valence-Shell Electron-Pair Repulsion” or “Molecular Geometry” in the index. Your book can also
assist in identifying functional groups in organic molecules.
1.
Draw Lewis structures for each of the given molecules. Name the VSEPR geometries and
identify the bond angles in each.
H2O NH3 HF HBr
HI CH4 CH3Cl CH2Cl2 CHCl3 CH3OH
2. Complete the table for 3 carbon organic molecules.
Molecule + Draw
the Lewis Diagram
CH3CH2OH
Line Drawing
Sketch of Geometry
(Label VSEPR bond angles)
Identity of functional
group
CH3COCH3
CH3CH2CHO
CH3CH2COOH
CH3CH2CH2NH2
CC-3
Experiment CC-1: Molecular Orbital Calculations of Small Molecules
(JK, AEK, WLE, JCW: 7/5/04)
Modified by Phil Palko 12-10-10
Background: Molecular Orbital Theory
While the VSEPR model allows us to predict qualitatively the most probable structure and the polarity
of a molecule, molecular orbital (MO) calculations offer more quantitative approaches to molecular
modeling.
MO calculations are based on quantum mechanical principles and thus, an MO calculation solves the
Schrödinger equation for a molecule. The Schrödinger equation is discussed in more detail in
advanced chemistry courses. For the purposes of this course, however, it is important to know only
that the Schrödinger equation for the hydrogen atom can be solved exactly and the solutions are the
energy levels and the corresponding atomic orbitals (eg., s and p orbitals) of the hydrogen atom.
But, unlike the H-atom Schrödinger equation, Schrödinger equations cannot be solved exactly for any
other atoms beyond helium. Thus, most MO calculations employ approximations. The various types
of MO calculations differ in the extent of approximation as well as the mathematical form for the
atomic orbitals used to perform the MO calculations. Regardless of the type, the final output of the
MO calculation is a set of MO energies and a corresponding set of MO's. The total energy of the
molecule can also be calculated. The energies of molecules that are calculated will be negative values.
Since molecules prefer the lowest energy state possible, the most stable molecules are the ones with
the most negative energy values.
Software that performs MO calculations solves the Schrödinger equation iteratively. Starting from an
initial “guess” geometry (usually entered by the user), the program solves the Schrödinger equation for
the initial geometry and obtains the total energy of the molecule. This is followed by varying the
geometry and solving the Schrödinger equation for the new geometry and so on, until the total energy
of the new geometry does not go below that of the previous iteration. This procedure of calculating the
total energy as a function of geometry is referred to as “geometry optimization” and the minimumenergy geometry is referred to as the “optimized geometry.” One should note that geometry
optimization procedures may give a false minimum-energy geometry. Often this occurs at a local
minimum or a saddle point. One can test for this by repeating the geometry optimization starting from
a different initial geometry.
Spartan
Spartan contains various levels (types) of MO calculations with a visual user interface. This visual
interface allows a user to enter an initial geometry and to view the optimized geometry. Spartan also
calculates various physical parameters - e.g., dipole moment, molecular volume, bond length, etc. from the optimized geometries and the MO’s
CC-4
To start Spartan:
Use the START button in the lower left corner to select the program Spartan ES. Open a new file by
selecting New in the pull-down menu File.
The general MO calculation procedure using Spartan to find bond lengths and angles:
1. Build the desired molecule using the palette on the right side of the monitor screen. Either the
Entry (Ent) model palette or the Expert (Exp) palette can be used. To do this click on the atombond type you need from the palette then click anywhere on the open space in the build window to
place the atom. Click on the next atom-bond type you want to use from palette, then click on the
small stub that represents the attachment point on the atom already in the build window to connect
the second atom. Repeat this as many times as needed to complete the model of the molecule.
2. When your molecule is built, select Build  Minimize in the main menu. (This performs a simple
molecular mechanics calculation to save time in the MO calculation.) The geometry from this
simple calculation is then used as the input to the MO calculation. The progress bar at the bottom
of the screen will fill part way and stop. Click in the build window to clear it once it stops moving.
3. Next, select Setup  Calculation from the main menu. In the dialog, select Equilibrium
Geometry (for the minimum-energy geometry) from the top menu to the right of “Calculate” and
select Semi Empirical, AM1 as the method of calculation. Leave the other selections in the
Calculation dialog as the defaults (unless instructed otherwise by the instructor) and click on OK.
4. Click Submit from in the bottom right of the box. For your first molecule you will be asked for a
file name for saving - give an arbitrary file name such as your name or locker number. This will be
a scratch file used through this experiment.
5. Depending on the size of the molecule(s) being studied, calculations may take several second,
minutes or even hours. Spartan will tell you when a calculation has started, and when it has
finished. The CPU time required for a particular calculation can be found in the output file, which
can be viewed by selecting Display  Output from the main menu.
6. You can also find the dipole moment by selecting Display  Properties from the main menu. In
the display box will be the dipole moment. By clicking on the checkbox next to it you can see the
dipole arrow displayed on top of the molecule.
7. To display a bond length or a bond angle, select Geometry  Distance or Angle in the main
menu. Select (by left-click) two atoms for a distance OR select three atoms (in an appropriate
sequence) for a bond-angle. The bond lengths and the angles are displayed in the lower right
corner of the monitor screen. A bond length can also be determined if you select the bond itself.
8. When you are finished with a molecule, click “Edit  Clear” from the main menu. Spartan will
reuse your saved file, and you won’t be prompted for filenames again.
CC-5
The general MO calculation procedure using Spartan to find dipole moments and electrostatic
potential maps:
1. Build the desired molecule using the palette on the right side of the monitor screen. Either the
Entry (Ent) model palette or the Expert (Exp) palette can be used. To do this click on the atombond type you need from the palette then click anywhere on the open space in the build window to
place the atom. Click on the next atom-bond type you want to use from palette, then click on the
small stub that represents the attachment point on the atom already in the build window to connect
the second atom. Repeat this as many times as needed to complete the model of the molecule.
2. When your molecule is built, select Build  Minimize in the main menu. (This performs a simple
molecular mechanics calculation to save time in the MO calculation.) The geometry from this
simple calculation is then used as the input to the MO calculation. The progress bar at the bottom
of the screen will fill part way and stop. Click in the build window to clear it once it stops moving.
3. Next, select Setup  Calculation from the main menu. In the dialog, select Equilibrium
Geometry (for the minimum-energy geometry) from the top menu to the right of “Calculate” and
select Semi Empirical, AM1 as the method of calculation.
4. Leave the other selections in the Calculation dialog as the defaults (unless instructed otherwise by
the instructor) and click on OK.
5. Click Submit from in the bottom right of the box. For your first molecule you will be asked for a
file name for saving - give an arbitrary file name such as your name or locker number. This will be
a scratch file used through this experiment.
6. After each optimization of the geometry, an electrostatic potential map can be obtained by
selecting Surfaces from the pull-down menu Setup. In the dialog, click on Add, then select
density (for the Surface) and potential (for the Property). Select the highest (slowest) resolution.
Click on OK and select Submit in the pull-down menu Setup. A map may require a minute or so
of computation.
7. When the calculation has completed, select Surfaces from the Display menu. In the dialog, select
the surface you want to display. Select the desired display-style (solid, mesh, etc.) by clicking on
the displayed surface and using the menu on the lower right corner of the monitor. The surface
represents the shape of the molecule and the color indicates the electrostatic potential on the
surface. The potential is coded from most negative (electron rich = red) to most positive (electron
poor = blue). A molecule on the screen can be rotated by left-clicking on the molecule and
dragging the mouse in a rotating motion. The polarity of a molecule can be predicted by
examining the electrostatic potential map, keeping the color coding in mind. If the electron
distribution is symmetric around the nuclei, the color distribution will be symmetric also
8. In order to obtain the value of the dipole moment from the MO calculation, select Display 
Properties from the main menu and read the computed dipole moment. (To get “molecular
properties” instead of “surface properties,” click on the electrostatic potential map while the
Properties pop up window is present.)
9. When you are finished with a molecule, select “Edit  Clear” from the main menu.
CC-6
Procedure for examining conformations in Cyclohexane:
1. Build cyclohexane using a model kit and identify the axial and equatorial positions.
2. In the Entry builder palette, select cyclohexane in the Rings menu.
3. To make methyl cyclohexane with the methyl group in the equatorial position, add a carbon
(which will be the methyl group) to any of the six equatorial positions.
4. Select Build  Minimize in the main menu. Next, select Setup  Calculation from the main
menu. In the dialog box, select Equilibrium Geometry, Semi-empirical, and AM1; use the
default setting for other selections in the Calculation dialog and click Submit. Obtain the total
energy (under Display, Properties). Note: Sometimes Spartan gives an error message that the
calculation has failed. Check the output file – sometimes this means that the energy has only
coverged to three or four decimal places (which is sufficient for our purposes) instead of eight
or nine. Use the energy value from the last iteration.
5. Repeat 1-4 but place a methyl group in the axial position.
Procdure to compare molecules with expanded octets:
1. Build your molecule using the Expert builder palette on the right side of the monitor screen,
because the Entry kit does not allow octahedral, etc., templates. Note that you must select the
number of electron pairs for the atom and then the identity of the atom using in the mini-periodic
table before placing the atom in the build window. Also, be sure to remove the stems represent
nonbonding electron pairs from the geometry, using the Delete Atom button which looks like a red
star in the tool bar and then click on the stem. Otherwise, Spartan will automatically attach H’s to
these bonds. You can also select Build  Delete from the main menu, then click the stem to
remove it.
2. Next, select Setup  Calculation from the main menu. In the dialog, select Single Point Energy
from the top menu to the right of “Calculate” and select Hartree-Fock, 6-31G* as the MO method.
The Single Point Energy will give you the energy of a particular geometry.
3. Click Submit or select OK and then Setup  Submit from the main menu.
4. Obtain the total energy (under Display, Properties) of each idealized geometry and deduce the
best structure for the molecule by finding the one with the lowest energy. Compare the lowest
energy structure with that of the VSEPR prediction and with the known structure. On your lowest
energy structure, do a second calculation to find “Equilibrium Geometry”. Record the bond angles
of the resulting structure. Note that alternatively, you could do an “equilibrium geometry”
calculation for each idealized structure, and compare the energies of the resulting distorted
structures.
An example of the results you will obtain in Part III is shown in the Example Table I below for the
polyatomic ion, triiodide, I3. Do not use this as your molecule since this molecule required more than
eight hours of computational time for the three possible molecular geometries.
CC-7
Table I Example Results Table for I3.
Molecule
LewisPossible
Optimized
VSEPR
Arrangement Bond Angles
structure s and VSEPR from Spartan
bond angles
Energy
(hartree)
I3
I-I-I Bond
Angle =
79.02°
20663.76205
I-I-I Bond
Angle = 120°
20663.73701
I-I-I Bond
Angle = 180°
-20663.849006
I
I
I
I
I
I
I
I
I
Best
Structure by
3-21G*
(highlighted
at left)
(I-I) bond
= 2.9762
angstroms
and I-I-I
bond angle is
180°
Experiment
allydetermined
Structure
Linear
I
I
I
1 hartree = 2625.46 kJ/mol
Guidelines:
Be sure to use the structures you documented in the prelab as you answer the questions in the
procedure. You can “go off the list” if your group wishes to explore other molecules. You will need to
plan with your group which molecules are best suited to provide information to address each question.
Some molecules will work for multiple questions. Special instructions for building specific molecules
and for performing tasks within Spartan are found in this handout. Follow these procedures! Provide a
table of information collected to answer each question. Part the assessment of your work will be the
quality of the data tables in your report.
CC-8
Procedure:
Question 1: How does electronegativity difference affect the dipole moment of a molecule? (Sketch the
electrostatic potential map of the molecules used to investigate this question and explain the sketches).
The classic example of a polar molecule is HF. Fluorine is the most electronegative element on the periodic
table (be sure you know what that means). The dipole moment of a molecule is a measure of that molecule’s
polarity. Look up electronegativity values in this lab handout. Use Spartan to determine he dipole moment of a
molecule. Initially, stick with simple heteronuclear diatomics so in addition to HF, use HCl and HBr. As
molecules become more complex, the relationship of electronegativity difference to dipole moment is more
complex. Compare the dipole moments of CH4, CH3Cl, CH2Cl, and CHCl3.
Question 2: What factors determine bond length?
Compare the carbon to carbon bond lengths in alkanes (C2H6), alkenes (C2H4), and alkynes (C2H2). Additionally
examine the effect of atom size on bond lengths. Create various halo-alkanes and compare the C-halogen bond
length. Use your textbook or the Internet to obtain the atomic radii for the atoms. You can also look at more
complicated organic molecules to determine if a C to C single bonds are the same length.
Question 3: Are all the bonds around an sp3 hybrid atom always 109.5? What factors determine the bond
angles?
CH4 is a simple example of a molecule with an sp3 atom, the carbon in this case. Create other simple molecules
such as CH3OH, CH3Br, H2O, and NH3, etc.. Examine the bond angles and see if you can find reasons why they
vary.
Question 4: How does changing the functional group in a molecule alter its properties?
First, decide what molecular properties can be compared using Spartan. You have already compared dipole
moments. Spartan can calculate molecular volumes, area, etc.
Construct a series of 3 carbon organic molecules but change the functional group for each. Start with ethane,
C2H6. Then create an alcohol, aldehyde, carboxylic acid, ketone and an amine, each with only 3 carbons. Use
the pre-lab as a guide!
Question 5: What conformation of methyl cyclohexane is most stable?
Here, you can compare the energy of the two conformations, one with the methyl group axial, the other
equatorial. Remember that the most negative energy means most stable.
Question 6: How does the position of lone pairs in molecules with expanded octets affect a molecule’s stability?
Compare stability of axial and equatorial positions of lone pairs in SF4 or ClF3 by building structures with the
lone pairs in different positions.
CC-9
Report Tutorial: Experiment CC-1: Introduction to PC Spartan
In your report, use all the headings that appear below in BOLD. Italicized notes in this tutorial are
guidelines to help you complete the report, so do not include these notes in your report.
Title of Experiment __________________________________
Report Submitted by _________________________________
Date Submitted ______________________________________
Purpose:



To learn how to use PC Spartan to obtain information about simple molecules.
To learn to identify basic organic functional groups and interpret line drawings.
To examine and compare characteristics of small molecules.
Procedure:
There is no need to report the steps you took in using Spartan as those are already outlined in the lab
handout. You should briefly outline the general steps your group took to answer each question.
Data and Results:
Create a table of relevant information that would include each molecule examined as you answered
each question. You will create 6 separate tables. Be sure each is adequately labeled!
Conclusion:
Provide a complete answer to each question posed in the experiment. Be sure to use your collected
data to support each answer.
CC-10
CC-2: : Synthesis and Purification of Aspirin and Comparison of its Acidity to Salicylic Acid
Using Molecular Orbital Calculations
Pre-Laboratory Assignment
Answer the following questions in your lab notebook.
1. Functional Groups. Redraw these structures in your lab notebook. Encircle the carboxylic
acid group in the following compounds. Underline the acidic hydrogen and point an arrow to
the carboxylic acid carbon. Write the ionization reactions for each of these acids.
2. Calculation practice Consider the following reaction, written (in part) using structural
formulas. (Recall that junctures imply a carbon atom, and that carbon forms four bonds to
complete its octet. Where fewer than four bonds radiate from a junction, implied hydrogens fill
out the structure. So a simple pentagon would have implied formula C5H10 .)
+
Phthalic acid
2 CH3OH
methanol

+
dimethyl phthalate
2 H2 O
water
(a) Write the molecular formulas for phthalic acid and dimethyl phthalate.
(b) Calculate the percent yield of the reaction if 4.3 g of phthalic acid and 0.29 g of methanol
produced 2.0 grams of dimethyl phthalate.
3. Understanding recrystallization. What is recrystallization? During recrystallization, which
would you want to dissolve more in the solvent, the impurities or your product? Explain your
answer.
Suppose you synthesized a certain compound which is less polar than one of your starting
materials, which include acetic acid. If you had the choice of two solvents, ethanol or hexane,
which one would you use to purify your product of any impurities (including acetic acid) by
recrystallization. Explain your choice.
acetic acid
CH3CH2OH
ethanol
hexane
4. If Acid A has pKa = 3.5 and Acid B has pKa = 2.3, which of the two acids is more acidic?
CC-11
EXPERIMENT CC-2: Synthesis and Purification of Aspirin and Comparison of its Acidity to
Salicylic Acid Using Molecular Orbital Calculations
(L. Herold, J. Sterrett)
Background_______________________________________________________________________
Recall from the scenario of page CC-2, that salicylic acid as a pain reliever has two nasty side effects,
it tastes terrible and it causes gastric irritation. Felix Hoffman, a chemist for Friedrich Bayer, became
interested in creating the modern version of aspirin when his father complained about the side effects
of salicylic acid. Hoffmann hypothesized that the acidic nature of salicylic acid could be reduced by
the substituting an acetate group, OCCH3, (from acetic anhydride) for the hydrogen in the OH group
directly attached to the ring.
HO
O
HO
O
OH
CH3
O
O
Salicylic Acid
Aspirin
As an intern at Pharm Tech, your boss has assigned you the task of trying out a relatively simple
computational chemistry software program called Spartan. You are to find out if Spartan could have
been used by Hoffman, if it had been available during his time, to predict if aspirin would indeed be
less acidic than salicylic acid.
Acids, as you have learned, are substances that give off the hydrogen ion in aqueous solution. Mineral
acids have a general formula of HA where H+ is a hydrogen ion and A stands for an anion. Examples
of strong mineral acids are HCl, HNO3 and H2SO4. The latter two are referred to as oxyacids, or acids
with anions with a central atom attached to oxygen atoms. Strong mineral acids completely ionize
according to the following scheme:
HA(aq)

H+(aq)
+ A (aq)
There are also organic acids and they have a general formula of
, or RCOOH, where R is a
carbon chain (either linear or cyclic). The organic acids have as their functional moiety the carboxylic
acid group, COOH. The acidic hydrogen is the one attached to the oxygen. It also has a carbonyl
(C=O) group attached to the OH. Organic acids are weak acids since they only partially give off their
hydrogen ion in aqueous solutions; most organic acid molecules hold onto the acidic hydrogen. Both
salicylic acid and aspirin contain this carboxylic acid group. Organic acids ionize in the following
manner:
O
Anion
+
H+
hydrogen ion
CC-12
Thus, when a molecule dissociates or gives up its hydrogen ion in aqueous solution, it generates two
species, namely the anion (negatively charged species) and the positively charged hydrogen ion. The
double arrow indicates that the forward and reverse reaction occur, with the forward reaction occurring
only to a small extent. One can compare the "strength" of different acids (their ability to release the
hydrogen ion) using their pKa values. pKa is the negative logarithm of the acid dissociation constant
Ka. You will learn more about Ka and pKa when we get to the chapter on acids and bases in this
course. For now, it is sufficient for you to know that the smaller the pKa, the more acidic the molecule.
To give you a complete experience of how the drug industry operates, you will also be synthesizing
acetylsalicylic acid (aspirin), through an organic synthesis (Part I) and purifying it by
recrystallization (Part II) in this experiment. You will also determine in Part III the dipole moments
and energies of salicylic acid, aspirin and ethanol using Semi-Empirical AM1 molecular orbital
calculations (you have used these before in experiment CC-1). These two parameters will be used to
justify the choice of ethanol as a recrystallization solvent and also to find the most stable conformation
of salicylic acid and aspirin.
In Part IV of this experiment, you will be performing Hartree-Fock calculations to determine three
parameters, the charge on the acidic proton, the charge on the carboxylic carbon and electrostatic
potential, of salicylic acid and aspirin. You will be using Excel to plot known pKa values of ten
carboxylic acids versus their respective previously computed data for the same three parameters. You
will then use the line formula of the parameter which gives the best correlation with the pKa to
determine the pKa values of salicylic acid and aspirin. You will be substituting the respective value of
the parameter you obtained using Hartree Fock calculations for these two acids into the line formula.
(This approach has been adapted from a method developed by Dr. Jim Peploski, Clarkson University).
We have chosen these three parameters among many possible ones since the strength of the acid can be
correlated to how large the partial positive charge on the hydrogen ion is and also to how large the
partial negative charge on the anion is.
1) Charge on the acidic proton – The O-H bond is polar with one atom possessing a partial
positive charge (the hydrogen) and the other (oxygen) a partial negative charge. The
strength of the acid is related to how electron-poor or how large the partial positive
charge is on the acidic hydrogen. The presence of electron-withdrawing or electrondonating groups in the molecule will affect this bond polarity.
2) Charge on the carboxylic acid carbon atom – The carbon on the carboxylic acid group
COOH can be compared to the central atom of an inorganic oxyacid like HNO3 and
H2SO4. The more electron-poor the central atom, or the larger the partial positive
charge it has, the more acidic the compound. The presence of electron-withdrawing
atoms like oxygen or other electron-withdrawing groups attached to the carbon of the
carboxylic acid group increases the partial positive charge of the carbon.
3) Electrostatic potential – The program Spartan is capable of determining the electronic
potential map of a molecule which shows the charge distribution in the molecule. The
electron distribution in a molecule can give an insight into the physical and chemical
properties of molecules including the strength of its acidic properties. Electrostatic
potential is the potential felt by a negative point charge located at a fixed distance from
the molecule. The larger the negative charge and the closer it is to a dipole created by
an electron-withdrawing group, the more stable the anion and in turn the more acidic
the compound is.
CC-13
The Organic Reaction
Aspirin is commonly synthesized by an organic reaction that results in the replacement of a hydroxyl
group, OH, on salicylic acid with an acetate group (OOCCH3). This reaction is commonly
performed by reacting salicylic acid with acetic anhydride in the presence of sulfuric acid or
phosphoric acid. Heat and sulfuric or phosphoric acid are used to catalyze the reaction.
Purification by Recrystallization
The products from many organic syntheses need to be purified, as they often contain contaminants
from competing side-reactions and unused starting materials. One commonly used laboratory
technique to purify the products of organic synthesis is recrystallization. Recrystallization involves
dissolving the reaction product into a solvent. The desired product is then forced to crystallize
(commonly through sudden cooling, or through the addition of a seed crystal). The resulting crystalline
organic material is often very pure. In aspirin synthesis, the major impurity, salicylic acid, is more
soluble in ethanol than the desired product, acetylsalicylic acid. This is due to the fact that salicylic
acid is significantly more polar than acetylsalicylic acid and ethanol is also very polar, and as we have
learned “like dissolves like”. During recrystallization, the salicylic acid impurities stay dissolved in
the ethanol while the desired product crystallizes out of the solution when the temperature is quickly
lowered.
Synthesis Technique
In this experiment, acetylsalicylic acid (aspirin) will be synthesized by reacting salicylic acid with
acetic anhydride. The reaction will be helped along by heat from a hot water bath. Once the reaction is
complete, the product will be purified through recrystallization.
Safety: Acetic anhydride is strongly corrosive and can cause serious burns. It is poisonous and will
cause serious damage if swallowed or inhaled; it can react vigorously or violently with water or
alcohols. Concentrated phosphoric acid can also cause severe burns. Wear your safety glasses
throughout this lab. Do not allow these liquids to contact your skin. Do not breathe the fumes!
CC-14
Procedure_________________________________________________________________________
PART I: Synthesis of Aspirin
1. Start a water bath immediately upon arrival in lab: fill a 400 mL beaker half way with water and
start heating it on a hot plate.
2. Weigh out 2.5 grams salicylic acid (record your mass to 0.001 g) and put it in a DRY 125 mL
Erlenmeyer flask. AT THE HOOD, measure out 3.0 mL of acetic anhydride (your instructor or TA
will do this with a pipette pump on the reagent bottle). Add this to the flask and swirl the mixture
until the reagents are well mixed. Be careful not to get the acetic anhydride into your hands.
3. Add 3 drops concentrated sulfuric acid and swirl the flask to mix its contents. BE CAREFUL.
Sulfuric acid is highly corrosive. Clamp the flask so that it is sitting in the boiling water of your
water bath. Let it heat in boiling water for 20 minutes. Watch the reaction while you are doing
other things during the waiting time. During the waiting time do step 4. Set up also the vacuum
filtration apparatus in step 7. During the waiting time start the calculations specified in Part III and
even Part IV. In fact do the calculations during the other waiting times that you will encounter
during the synthesis and recrystallization of aspirin.
4. Prepare an ice bath by filling a 600 mL beaker 1/2 full with ice. Add distilled water to the ice to
fill the air spaces but still keeping the total volume to 1/2 of the beaker. Set aside the ice bath for
future use. Place a wash bottle with distilled water in a common water bath consisting of a bin or
pail with ice/water to be set up by your instructor.
5. Once the reaction has completed warming for the specified time, remove the reaction vessel from
the hot water bath (see note) and chill it in the ice-water bath for 10 minutes so that crystallization
is complete. If no solid appears at all during this time try scratching the bottom of the flask with a
stirring rod until the solution becomes cloudy and solid appears. (Note: You will be using the
water bath later on in Part II of the experiment. Be sure to replace the water in the water bath by
filling the beaker half way with water and continue warming it. Be sure to replenish it with water
when the level gets lower than half way full during waiting times.)
6. Add approximately 25 mL of chilled distilled water from the previously chilled wash bottle of
distilled water to the reaction mixture and mix it with a stirring rod. If necessary, break up any
hard, chunky solid with a scoopula. You are ready to filter and isolate your solid crude product by
vacuum filtration.
7. Set-up a vacuum filtration apparatus as you have done before (be sure to clamp your vacuum
filtration flask to the iron stand). Weigh the filter paper on a watch glass. Record their combined
mass in your notebook. Then place the filter paper in the Buchner funnel, and set aside the watch
glass for later use.
8. When you are ready to use the vacuum filtration apparatus, be sure the filter paper covers all the
holes in the Buchner funnel and is seated firmly and flat to the bottom of the funnel. Dampen the
filter paper with a little amount of water from the wash bottle in order to hold it in place. Turn on
the water tap of the aspirator on full force to start the vacuum. Carefully swirl the reaction mixture
in the flask and pour the contents of the reaction vessel into center of the paper. Using a minimum
CC-15
amount of chilled distilled water from the wash bottle, wash the sides of the flask, pour the wash
into solid in the funnel of the vacuum filtration apparatus. Let the solid air dry on the filter paper,
with the aspirator running, for about 5 minutes.
9. Using a spatula, carefully transfer the filter paper together with the product from the funnel and
onto the watch glass you had previously weighed with the filter paper. Obtain and write their
combined mass in your notebook. Using a spatula remove the crude product from the filter paper
and into a 125 mL Erlenmeyer flask. Immediately proceed to Part II to purify it via
recrystallization so as not to lose time. (You can calculate the percent crude yield later on.)
PART II: Purification of Reaction Product via Recrystallization (completed only if time allows)
1. Add 10 mL of ethanol to the crude product obtained in Part I. (Note ethanol is highly
flammable and should not be used near an open flame.)
2. Gently warm the solution on the hot water bath (see note) until the solid has completely
dissolved. Do not allow the solution to boil. Note: If you forgot to set up the hot water bath
you can also heat the flask directly on top of the hot plate set at medium setting.
3. Slowly add 20 mL of room temperature distilled water and continue heating for 5 minutes or
until any solid dissolves. Do any further calculations in Part III or IV during any waiting times.
4. Remove the flask from the water bath and allow the reaction mixture to cool on the desktop for
1-2 minutes then place it in an ice bath (be sure it has been replenished with more ice) for 5
minutes or until the amount of precipitate does not seem to increase with time. If no precipitate
forms in 5 minutes or so scratch the bottom of the flask until the solution turns hazy and solid
forms.
5. Place a new filter paper that has been previously weighed together with a clean watch glass into
a clean Buchner funnel on the vacuum filtration apparatus.
6. Slowly pour the contents of the reaction flask in the funnel of the vacuum filtration apparatus.
Using a minimum amount of chilled distilled water from a wash bottle, wash the sides of the
beaker and pour the wash into the solid in the funnel of the vacuum filtration apparatus. Let the
solid air dry on the filter paper, with the aspirator running, for about 5 minutes or more till it is
dry.
7. Using a spatula, transfer the filter paper together with the recrystallized product from the funnel
and into the watch glass you had previously weighed together with the filter paper. Obtain and
register their combined mass in your notebook. Calculate the percent yield of the recrystallized
or purified product and write it in your report.
8. Once you are done with the final weighing of your purified product dispose of it in a waste
container in the hood provided by your instructor. In the preparation of any drug in the
pharmaceutical industry more steps are involved which we have no time to perform in this
experiment to ensure the safety of its use by the consumer. Among these is the determination
of the purity of the product using various techniques including chromatography to find out if
any unreacted starting materials or side products are present. You will use paper
CC-16
chromatography in a future experiment using a different set of compounds. In a future course,
Organic Chemistry, you will learn spectroscopic techniques like Nuclear Magnetic Resonance
and Infrared Spectroscopy to characterize the compound you have synthesized to prove that its
structure is what it is intended to be.
Part III. Determination of the Dipole Moment and Energies of Salicylic Acid, Aspirin and
Ethanol.
Using Semi-Empirical AM1 molecular orbital calculations, calculate the polarity (dipole moment)
and energies of salicylic acid, acetylsalicylic acid (aspirin), and ethanol, and record your results in a
table. section. Please refer to Experiment CC-1 for the computational procedure (page CC-6). Be
sure to build the molecules as shown in Table 1 provided in the report tutorial. Changes in
conformation will affect the calculations. Based on your data choose the best stable conformation for
salicylic acid and aspirin. Use these conformations in part IV.
Part IV. Determination of the H Charge, C Charge, Electrostatic Potential Parameters and
pKa of Salicylic Acid and Aspirin.
A. Determination of the H Charge, C Charge, Electrostatic Potential Parameters by HartreeFock calculations. You will use Hartree-Fock to calculate the H Charge, C Charge and
Electrostatic Potential of salicylic acid and of aspirin using the following two main steps. After
you finish Part A you will then proceed to Part B to determine the pKa of salicylic acid and aspirin.
1) Building a Molecule:
Open Spartan and click on File in the header menu. Click on New. The builder menu will appear
on the right side of the screen. Begin construction of the most stable conformation of the molecule
(first do salicylic acid and then aspirin).
When the structure is complete, click on Build in the header menu and then on Minimize. This
will perform a crude optimization of the molecular geometry. Save the final structure by clicking
on File and then on Save As. Give your file a name and click on Save.
2) Optimizing the structure and performing Hartree-Fock Calculations:
To set up an ab initio optimization of the molecular geometry, select Setup and click on
Calculations. In the Setup Calculations window, the top box should read: “Calculate: Equilibrium
Geometry at Ground state with Hartree-Fock 3-21G*.” Click OK.
Set up a calculation of the electrostatic potential by selecting Setup and Surfaces. Click on Add.
For surface, select Density and for property, Potential. Click OK. Close the Surfaces List window.
Start the calculations by clicking on Setup and Submit. Click OK when the notification windows
(two) appear. When the job has completed, click on Display and Properties. Click on the
hydrogen atom on the acidic (-OH) group. Record the value listed under Electrostatic Charge in the
Atom Properties window in your lab notebook. Click on the carboxylic acid carbon atom and
record its electrostatic charge in your lab notebook.
CC-17
To determine the electrostatic potential in the vicinity of the acidic hydrogen atom, display the
electrostatic potential surface by clicking on Display and Surfaces. Click in the yellow box and
close the Surfaces List window. A colored surface will appear around the molecule. Blue areas
indicate regions of greatest positive charge and red areas indicate regions of greatest negative
charge in the molecule. Click anywhere on the colored surface. A box will appear at the bottom,
right-hand corner of the screen. For style, select Transparent. Click in the surface in the vicinity
of the acidic hydrogen atom. Click on Display and Properties. The Surface Properties window
will appear. Record the positive value shown in the Property Range box in your notebook - include
the units!
B. Determining the pKa of Salicylic Acid and Aspirin
You have just obtained the data for the H charge, C charge and Potential for salicylic acid and aspirin
using Hartree-Fock calculations in Part IV A of this experiment. Before you can calculate the pKa of
salicylic acid and aspirin, you will need to determine first which of the three parameters will be used to
determine the respective pKa of salicylic acid and aspirin. In order to accomplish this, you will need to
use Excel to graphically analyze the relationship of the pKa with each of the three parameters (H
charge, C Charge and Potential) using previously calculated data of ten carboxylic acids shown in
Table A on page CC-20. From your Excel data you will decide which of these three properties relates
best to the pKa (namely the one with the best correlation value or the most linear) and use the line
formula of the plot of this parameter to determine the pKa.
1) Using Excel, plot the pKa values of the ten organic acids on the y-axis against each
of the three parameters (x-axis) provided in Table A on page CC-21. The three
plots that you will be generating using the data on Table A are:
pKa vs H charge
pKa vs C charge
pKa vs Potential
2) Obtain the linear equation and correlation factor (R2) of each of the plots.
Determine which of the three parameters give the best correlation with pKa (namely
the one with the R2 value closest to 1). Use the formula of the line for this parameter
to determine the pKa of the salicylic acid and aspirin by substituting the respective
values of this parameter that you previously obtained for salicylic acid and aspirin in
Part IV.A into the line formula. Place your answers in the report. Show also the
calculations of the pKa of salicylic acid and aspirin in the data sheet and the percent
error. Attach the three Excel plots to your report.
CC-18
Table A. Hartree-Fock Computational Data of Parameters of Ten Organic Acids
#
Molecule
pKa
H
C
Potential
Charge Charge
1
0.7
0.535
1.01
91.1535
1.48
0.526
1.022
82.4621
2.45
0.501
1.062
79.3373
2.85
0.504
1.029
74.5318
3.75
0.518
0.873
72.4641
3.79
0.501
1.068
73.9398
4.25
0.488
1.064
73.7649
4.75
0.487
1.083
69.5049
4.78
0.497
0.943
70.1299
5.03
0.514
0.871
65.9126
2
3
4
5
6
7
8
9
10
CC-19
Report Tutorial: Experiment CC-2: Synthesis, Purification, and pKa Determination of
Acetylsalicylic Acid (Aspirin)
In your report, use all the headings that appear below in BOLD. Italicized notes in this tutorial are
guidelines to help you complete the report, so do not include these notes in your report.
Title of Experiment __________________________________
Report Submitted by _________________________________
Date Submitted ______________________________________
Purpose:
Use the scenario of the experiment group to summarize the purpose of the experiment in 1-2 sentences.
Procedure:
Who did what? Be specific about each part of the procedure.
For Parts I and II, list any changes to the given procedures.
Data and Results for Part I: Synthesis of Aspirin
 Create a data table that includes mass of flask, mass of salicylic acid and flask, and mass of
salicylic acid, mass of the watch glass and filter paper, mass of watch glass, filter paper and
crude product, mass of crude product.
 Show sample calculations for the moles of salicylic acid, theoretical moles of aspirin,
theoretical mass of aspirin, and percent yield of the crude product. Recall that sample
calculations show first show a word equation before the numbers are substituted. Watch
significant figures!
Data and Results for Part II: Purification of Reaction Product via Recrystallization (omit if not
done).
 Create a data table that includes mass of the watch glass and filter paper, mass of watch glass,
filter paper and recrystallized product, mass of recrystallized product. Show a sample
calculation for the percent yield of the recrystallized product.
Data and Results for Part III. Dipole Moments and Energies of Salicylic Acid and Aspirin
 Complete and submit Table 1 (appended).
 List which of the conformations are most stable for salicylic acid and aspirin.
Data and Results for Part IV. Determination of the H Charge, C Charge, Electrostatic Potential
Parameters and pKa of Salicylic Acid and Aspirin.
 Create a data table that lists each of these three parameters for salicylic acid and for aspirin
 Attach labeled (descriptive title, axes labeled) Excel plots of pKa vs each parameter for the ten
acids given in Table A (page CC-21 in the experiment).
 Decide and justify which parameter best correlates with pKa.
 Show sample calculations of the pKa of salicylic acid and the pKa of aspirin.
 Show a sample calculation of the % error for the pKa of salicylic acid from Hartree Fock
calculations (as compared to reference value of 2.97)
CC-20

Show a sample calculation of the % error for the pKa of aspirin from Hartree Fock
calculations (as compared to a reference value of 3.29)
Conclusion
Write a conclusion in your lab notebook, beginning with an opening sentence that summarizes what
you did and what you learned. Include in your discussion, in paragraph from, answers to the
following questions:
1. How did the yield in grams of crude product compare to the yield of recrystallized product? How
did the percent yields compare? Account for any differences. What technique errors would make
the percent yield of recrystallized product too high (over 100%)? too low (less than 70-80%).
2. Based on the polarities that were calculated using molecular orbital calculations in Part II,
formulate a rationale as to why ethanol is a good or poor recrystallization solvent for
acetylsalicylic acid. (omit this question if recrystallization was omitted).
3. Give reasons for the stability of the more stable conformation between two possible ones for
salicylic acid. Hint: examine the structure and determine what atoms that are not bonded to each
other are most adjacent. It is best not to have to highly electronegative atoms close to each other
due to repulsion effects.
4. Give reasons for the stability of the most stable conformation among four possible ones for aspirin.
5. Based on your Hartree-Fock calculations, where you able to verify if aspirin is less acidic than
salicylic acid? Explain.
6. Finally, make recommendations to your company about Spartan and address its strong points and
weaknesses.
CC-21
Table 1. Semi-Empirical AM1 Calculations of Dipole Moments and Energies of Salicylic Acid
and Aspirin
3-D sketch of
conformation from
Spartan
Molecule
Dipole Moment
(Debye)
Energy
(kcal/mol)
Salicylic Acid
Conformation I
HO
O
OH
Salicylic Acid
Conformation II
OH
O
OH
Acetylsalicylic
Acid
Conformation I
HO
O
CH3
O
O
CC-22
Table 1 Continued. Semi-Empirical AM1 Calculations of Dipole Moments and Energies of
Salicylic Acid and Aspirin
Acetylsalicylic
Acid
Conformation II
O
OH
CH3
O
O
Acetylsalicylic
Acid
Conformation III
HO
O
O
O
CH3
Acetylsalicylic
Acid
Conformation IV
O
OH
O
O
CH3
Ethanol
CC-23