Properties and Stability of Carboxylic Acid Derivatives
Thomas Painter
University of Pittsburgh
June 2006
Assignment Objectives
The goal of this assignment is to explore the electronic and thermodynamic properties of
acid derivatives. The student will observe trends and should be able to draw conclusions
on general stabilities of these compounds. This exercise should reinforce concepts
learned in class.
Section 1: Electronic Properties
In this section you will explore bond lengths, dipole moments, and electron density maps
of acid derivatives and discuss how these properties relate the known reactivity of these
compounds toward nucleophiles. Supplemental instructions on the use of the CAChe
program software package are provided at the end of the document.
1.)
Using CAChe, first build (i.e. draw) the following molecules. Minimize the
geometry of the molecule using PM3 geometry then find the lengths of all C-Cl, CN, C-O, and C=O bonds. Three simple molecules are shown along with their
calculated bond lengths for comparison. These calculations were done using PM3
geometry. Enter these data into the first part of Table 1. You will fill in the
remainder of the Table in the upcoming section.
Section 1 Data List
CH3-Cl
CH-OCH3
CH3-N(CH3)2
C-Cl = 1.76 Å
C-O = 1.42 Å
C-N = 1.48 Å
O
O
Cl
Table 1: Acid Derivative Electronic Data
Acid
Chloride
Length: C-Cl
C-O
Length: (C=O)
(C=O)
Dipole moment
Partial charge
O
O
N
Ester
Amide
C-N
(C=O)
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a.) Based upon the bond lengths, which molecule is least stabilized by resonance?
b.)
What can you infer about the reactivities of these molecules based upon resonance
stabilization? Are the calculations accurate enough to show a familiar reactivity
trend?
.
2.)
Using Project Leader, calculate the dipole moments and partial charges for the
carbonyl carbon atoms in the acid derivatives. (The row labeled “C2” gives the
partial charge). Enter the data into Table 1. Supplemental instructions on the use of
Project Leader are provided at the end of the document.
a.)
Which molecule has the largest dipole moment and why?
b.)
It seems intuitive that the molecule with the highest partial positive charge on the
carbonyl carbon atom would be the most reactive towards incoming nucleophiles
(electron sources). Using what you have learned in class, do the PM3 calculations
support this hypothesis? Why or why not?
3.)
A better method of visualizing trends in reactivity is through electron density maps.
These maps display amounts of electron density in all areas of a molecule through
coloration. Red means less electron density, while blue means a greater amount of
electron density. The most important factor to consider when judging a reactivity
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order is the expanse of red area found around a molecule’s active site. The larger
the red area, the more reactive the molecule should be toward nucleophilic attack.
a.)
Construct electron density maps of each molecule that you’ve drawn previously
(acid chloride, ester, and amide). Predict which molecule you would expect to be
the most susceptible to nucleophilic attack based upon where the most electron poor
regions are found. It would also be a good idea to attach screen shots (cropped as
needed) in your report.
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Section 2: Thermodynamic Properties
In this next section, you will explore the thermodynamic properties of acid derivatives
and discover the role that thermodynamics play in their reactivity toward nucleophiles.
Since transition states are difficult to model, use of the Hammond Postulate will be
necessary to make transition state comparisons using intermediates.
1.)
Use CAChe to draw the following molecules and minimize their geometries using
PM3 geometry. The using the PM3 calculation procedure, fill in the reaction
diagrams with heats of formation. Lastly calculate the ΔH for each system using
the calculated values.
a.)
O
HO
O
+
H
Cl
OH
H
Cl
Table 2
ΔHf
(kcal/mol)
ΔHrxn (kcal/mol) =
b.)
O
HO
O
+
H
O
OH
H
O
Table3
ΔHf
(kcal/mol)
ΔH (kcal/mol) =
c.)
O
HO
O
+
N
OH
H
H
N
Table 4
ΔHf
(kcal/mol)
ΔH (kcal/mol) =
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2.)
Use the values you obtained above to answer the following questions.
a.)
In going from the starting materials to the tetrahedral intermediate, which reaction
is most exothermic? Least exothermic?
b.)
Using only the data obtained in this exercise and by appealing to the Hammond
postulate, rank the acid derivatives in order of stability, least stable first. Explain
this in terms of the transition state.
Section 3: A Unique Synthetic Tool – the Weinreb Amide
Named after the person who invented it, Professor S. M. Weinreb of Penn State, this
amide presents a unique reactivity that other amides do not. This amide has the
advantage of being more stable than an acid chloride, making it easier to work with,
while simultaneously being more reactive than an amide. You will explore the properties
behind this unique and synthetically useful compound.
1.) Fill in Table 5 using the same procedures you used in the previous sections and PM3
geometry.
O
O
N
Table 5
C-N
(C=O)
Dipole moment
Partial Charge
a.)
Compare the data for the Weinreb amide to the amide.
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2.)
Use the procedure from section 1 to construct an electron density map for the
Weinreb amide. Describe its appearance and how it compares to an amide. You
may also wish to paste a cropped screen shot of this molecule in your report.
3.) Fill in Table 6 using the same procedures you used in the previous sections and PM3
geometry.
O
HO
O
N
OH
O
+
H
O
H
N
Table 6
ΔHf
(kcal/mol)
ΔH (kcal/mol) =
a.)
How does the stability of a Weinreb amide compare to a standard amide
thermodynamically?
b.)
You can now rank the four acid derivatives in order of stability by appealing to the
Hammond postulate. Rank the four acid derivatives in order of stability, least stable
first.
4.)
What overall comparisons (both electronic and thermodynamic) can you make
between the Weinreb amide and an amide?
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Supplement to Properties and Stability of Carboxylic Acid Derivatives
Thomas Painter
University of Pittsburgh
June 2006
Minimizing and Finding Bond Lengths in CAChe Workspace
1.) In workspace, draw the desired molecule using the drawing tools.
2.) Use the select molecule tool and go to beautify/comprehensive from the dropdown menus.
3.) Go to experiment/new. It will ask you to save the molecule to a file. Select yes
and name the file something that you can easily access later.
4.) When the experiment menu comes up select: property of: chemical sample,
property: optimized geometry, Using: Standard procedure. This should default to
MM2 geometry, but this can be changed when needed. The select “start.”
5.) Once the molecule is minimized use the atom select tool and select an atom.
Then shift select an atom bonded to it.
6.) Go to Adjust/Atom Distance from the drop-down menu. The atom distance will
be listed in the box.
Calculating Dipole Moments in Project Leader
1.) Open the project leader program (see the CAChe folder under the program menu)
and double click the first gray cell under the cell (row 1) marked Chemical
Sample.
2.) Find the file (be sure to look in the same folder used to save the file above) with
the molecule for which you wish to calculate properties, select it and hit “ok”
3.) Do the same for any other molecules to create a list.
4.) Double click the gray cell at the top of the next column (column B).
5.) Select: property of chemical sample and click next.
6.) Select: dipole moment and click next. Then select dipole moment at PM3
geometry and select ok.
7.) Now highlight all white cells in the column for rows that have a Chemical Sample
file name identified and right click. At the bottom of the pop-up menu select
“evaluate cell.” This will populate the highlighted cells with calculated dipole
moments.
Calculating Partial Charges in Project Leader
1.) Follow steps 1-4 from calculating dipole moments.
2.) Select: Property of Atom then next
3.) Select: Charge Partial then next
4.) Select: partial chrg at PM3 geom, then hit ok
5.) A gray box will appear in the column you selected. Right click and evaluate this
box. A list of atoms appears
6.) The column next to this gray column will now house the partial charges once
calculated. Highlight all boxes and evaluate them. The carbons are numbered in
the order that you drew them. If you drew the carbonyl carbon first, it will be C1,
or C2 if you drew it second, etc.
Viewing Electron Density Maps Using CAChe Workspace
1.) Construct a molecule and minimize the geometry.
2.) Go to experiment/new in the drop-down menu
3.) Select: property of: chemical sample, property: electrostatic potential on electron
density; Using : MM geometry with PM3 wave function
4.) Select Start and save the file if prompted.
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5.) Once the calculation has completed, select Analyze/Show Surfaces from the dropdown menu.
6.) Check the entry with “EonD” at the end and select ok
7.) You can now view the electron density map for the molecule. Blue indicated high
electron density and red indicate low. Other colors are intermediate.
8.) You can see the surface legend by selecting the surface with the select tool then
going to Analyzed/Surface Legend from the drop-down menu.
Calculating Heats of Formation Using CAChe Workspace
Heats of formation are given in the calculation readouts when you calculate an optimized
geometry. Make sure to use PM3 geometry for this exercise.
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