Predicting the Reactivity of a Complex Molecule using the Heat of Formation and
Electrostatic Potential Calculations Generated by CAChe.
Jamie McCabe
Department of Chemistry, University of Pittsburgh
June 2006
Learning Objective:
The overall objective of this computational exercise is to introduce you to ways to use molecular
modeling to solve ‘real-life’ problems in organic synthesis. You will see how you can use
computational analysis to lead the direction of the reaction sequence instead of trying a reaction
in the laboratory and getting an undesired product.
Requirements to Complete Exercise:
Recommended for after students have completed a chapter on enolates and the aldol
condensations reactions in an organic text (e.g., Chapter 18, Organic Chemistry; Structure and
Function by K. Peter C. Vollhardt, 4th ed.).
Students may want to review the chapter of their organic text on kinetics and thermodynamics
(e.g., Chapter 2, Organic Chemistry; Structure and Function by K. Peter C. Vollhardt, 4th ed.),
and relevant prior exercises on molecular modeling (e.g., Chapter 5, The Organic Chemistry
Laboratory Experience at the University of Pittsburgh by George C. Bandik, 7th ed.) although
prior experience with computational packages is not necessary.
This exercise is designed for the CAChe software Package.
Introduction:
O
OHC
OH
AcO
Guanacastepene A (1)
Guanacastepene A (1) was isolated in 2000 from the fungal extracts found in the branch of a
Daphnopsis Americana tree located in the Guanacaste Conservation Area in Costa Rica. This
structurally diverse diterpene has shown excellent activity against methicillin-resistant S. aureus
(MRSA) and vancomycin-resistant E. faecalis (VREF) pathogens. This is a desirable attribute
due to the increasing number of cases in which bacteria are showing resistance to antibiotics.
1
Oxidation
O
1
O
O
O
OH
O
O
(1)
2
2
Aldol condensation
Figure 1
Because of its potential as an antibiotic, guanacastepene A is a popular synthetic target in many
research groups; including at the University of Pittsburgh. In one route towards Guanacastepene
A a tricyclic intermediate 2 is formed. Subsequently, both -carbons of the ketone need to
undergo a reaction each of which is different (Figure 1). Oxidation at C1 is required while an
aldol condensation is necessary at C2: both transformations require enolate formation of the
ketone moiety shown in figure 2. In this exercise you evaluate both the kinetics and
thermodynamics of this reaction using computational analysis which will identify the kinetic and
thermodynamic enolates of this reaction. This information will allow the student to decide which
reaction to do first (oxidation at C1 or aldol condensation at C2) and which reaction conditions to
use.
O
1
O
O
2
3
LDA
O
Li
O
O
O
E+
?
O
O
Li
4
E+
5
O
E
O
O
O
O
O
E
Figure 2
In exercise 1, you will evaluate the chemical kinetics associated with the deprotonation of the protons of the ketone moiety. Remember chemical kinetics looks at the speed at which a reaction
goes to completion or in this case which -proton will deprotonate the fastest. If this reaction is
under kinetic control, the product obtained is the one resulting from the kinetic enolate. To
determine which enolate 4 or 5 is the kinetic enolate, you will use CAChe to calculate the
electrostatic potential surface of the molecule. The electrostatic potential surface of a molecule
2
will identify regions of local (-) and (+) potentials in a molecule. In other words it reveals the
charge distribution that the reactant “sees” as it approaches a molecule.1
Exercise 1:
Build molecule 3a2 in CAChe and find the electrostatic potential surface of 3a by following the
instructions below, then answer the posed questions.
H3C
1
O
CH3
2
H3C
3a
CAChe Instructions:
Construct molecule 3a
Open / CaChe / Workspace.
Click Drawing pencil tool (5th down on left), and draw molecule 3a.Hint: Choose Beautify /
Comprehensive a few times while drawing structure 3a.
Click Select tool (1st down on left).
Click in workspace. Entire molecule should appear in full color. Note: if don’t like the way
molecule is presented on screen Choose View / (line only or cylinder)
Clean up structure by selecting Beautify / Comprehensive. All hydrogens should appear.
Calculate
First you need to optimize the geometry of 3a to find the lowest energy conformation.
Calculate the optimized geometry by selecting Experiment / New.
It will ask you to save file. Click yes and save as Guana3a.csf.
Choose Property of: Chemical Sample.
Property: Optimized geometry
Using: PM3 geometry.
Click start (the calculation will take a few seconds).
When the experiment is complete, the ‘Experiment Status’ window will read ‘calculation done’.
Close the ‘Experiment Status’ and ‘Experiment’ windows.
Calculate the electron density colored by electrostatic potential by selecting Experiment / New.
Choose Property of: Chemical Sample.
Property: electrostatic potential on electron density.
Using: PM3 geometry with PM3 wavefunction.
Click start. (the calculation will take a few minutes)
When the experiment is complete close the ‘Experiment Status’ and ‘Experiment’ windows.
View the electrostatic isopotential mapped onto the electron density by selecting: Analyze /
Show Surfaces
Select filename.EonD then click ‘OK’.
To understand what the colors mean, click once on the displayed surface so that it is “solid”.
Investigate the different viewing parameters by selecting Analyze / Surface Attributes and click
on “Wireframe” or “Dotted”, etc., to see the various display modes. (NOTE: To remove surface
select Analyze / Show Surfaces and deselect filename.EonD then click ‘OK’.)
1
2
For more information about the electrostatic potential refer to Appendix A.
For the purpose of this experiment simplified structures of Guanacastepene A intermediate will be used.
3
Select Analyze / Surface Legend. Study the legend.
The surface you are looking at is showing you the charge distribution of molecule 3a. The legend
reveals that the white areas have a partial positive charge associated with them, while the
purple/cyan areas have a partial negative charge.
1. Do the colors of the surface make sense?
2. Does the isopotential mapped onto the electron density tell you anything about which proton will deprotonate fastest / first?
3. Just based on the computational analysis of the electrostatic isopotential and assuming
that the reaction is under kinetic control, which reaction should the graduate student do
first (oxidation of C1 or aldol condensation of C2)?
In exercise 2 you will evaluate the chemical thermodynamics associated with the enolate
intermediates. Chemical thermodynamics deals with the change in energy that takes place when
a chemical reaction occurs; therefore, a reaction that yields the most stable products (or in this
case resulting from the most stable enolate) is said to be under thermodynamic control.
Remember, all chemical reactions are reversible, and reactant and products interconvert to
various degrees. For this example we are concerned with the equilibrium between the two
enolate intermediates formed from the deprotonation of the -protons on the ketone see figure 2.
You will use CAChe to determine the Heat of formation of each intermediate (4 and 5) and then
calculate the equilibrium constant.
Exercise 2:
Build molecule 4a and 5a3 in CAChe and find the Heat of Formation, ΔfH, of each by following
the instructions below, then answer the posed questions.
Li
H3C
H3C
O
CH3
O
CH3
Li
H3C
H3C
4a
5a
Construct molecule 4a
Draw molecule 4a by modifying structure 3a. VERY IMPORTANT: To get the coordination of
the lithium cation to the oxygen anion of the enolate you must connect them with an ionic bond
3
For the purpose of this experiment simplified structures of Guanacastepene A intermediate will be used.
4
and give each moiety a positive or negative charge. Make sure after you beautify there are no
hydrogens on the oxygen or lithium atoms.
Click Select tool (1st down on left).
Click in workspace. Entire molecule should appear in full color. Note: if don’t like the way
molecule is presented on screen Choose View / (line only or cylinder)
Clean up structure by selecting Beautify / Comprehensive. All hydrogens should appear.
Resave file under new name by selecting File / Save As and save as Guana4a.csf
Calculate
Calculate the heat of formation by selecting Experiment / New.
If it will asks you to save file, click yes.
Choose Property of: Chemical Sample.
Property: Heat of formation
Using: PM3 geometry.
Click start. (the calculation will take a few minutes).
When the experiment is complete, record the ΔfH value and close the ‘Experiment Status’ and
‘Experiment’ windows. Record the heat of formation here:
Now draw structure 5a by modifying structure 4a.
Click in workspace. Entire molecule should appear in full color. Note: if don’t like the way
molecule is presented on screen Choose View / (line only or cylinder)
Clean up structure by selecting Beautify / Comprehensive. All hydrogens should appear.
Resave file under new name by selecting File / Save As and save as Guana5a.csf
Calculate
Calculate the electron density by selecting Experiment / New.
It will ask you to save file. Click yes and save as Guana5a.csf.
Choose Property of: Chemical Sample.
Property: Heat of formation
Using: PM3 geometry.
Click start. (the calculation will take a few minutes).
When the experiment is complete, record the ΔfH value and close the ‘Experiment Status’ and
‘Experiment’ windows. Record the heat of formation here:
Equations:
ΔrxnG = ΔrxnH - TΔrxnS
ΔrxnG = -RT ln Keq
R = 1.987 cal/ mol*K
ΔrxnH = ΔfH5 - ΔfH4
Keq = [5] / [4]
For these calculations we are going to assume ΔrxnS = 0, since the change in entropy between the
two intermediates is negligible.
1. Using the ΔfH values found for 4a and 5a calculate the ΔrxnG and then calculate the Keq at
0ºC.
2. What does value of K tell you about the equilibrium process between the two enolate
intermediates 4 and 5?
3. Using only the information in this exercise will one enolate intermediate be formed
selectively and to what degree (what is the ratio of 4 : 5)?
4. If so, which one?
5. Just based on the computational analysis of the heat of formations of 4a and 5a and
assuming that the reaction is under thermodynamic control, which reaction should the
graduate student do first (oxidation of C1 or aldol condensation of C2)?
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