The Haloform Reaction: A mechanistic examination using computational chemistry
Ben Norris
Department of Chemistry, University of Pittsburgh
June, 2006
Learning goals:
In this assignment, you will explore the haloform reaction using computational chemistry. You
will use heat of formation calculations to understand the relative acidities of carbon acids, and
the implications these acidities have for the mechanism of the base-promoted -halogenation
reaction and the haloform reaction.
You should be generally familiar with enolate chemistry (Chapter 18 in Volhardt and Schore, for
example) before completing this assignment. You may wish to review acid/base equilibria, heats
of formation and enthalpies of reaction from your General Chemistry textbook before working
on this assignment. Previous experience with computational chemistry (such as that from the
Organic Chemistry Lab Course) is not required. A guide for using the CAChe program as it
pertains to this assignment is included in an appendix at the end.
Overview:
The haloform reaction is a reaction of a methyl ketone (a 2-alkanone) in basic solution in the
presence of excess halogen. The organic products of this reaction are the haloform
(trihalomethane) and a carboxylate anion. The overall reaction is shown below.
O
+
R
4 OH-
O
+
3 X2
+
R
CHX3
+
3 H2O
+
3 X-
O
The haloform reaction is unique to methyl ketones. Other ketones will undergo base-promoted
-halogenation, but will react no further.
If the halogen used is iodine, the reaction becomes the iodoform test reaction. Iodoform is a
bright yellow solid, and its formation can be used as a qualitative test for the presence of a
methyl ketone.
Part I: Base-promoted -halogenation
The first part of the haloform reaction is a base-promoted -halogenation reaction. This reaction
can be exhaustive – the presence of excess base and halogen can lead to multiple halogenations.
During the first part of this assignment you will use CAChe to examine why this reaction is
exhaustive.
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Exercise 1:
Draw the mechanism for the base-promoted -halogenation of acetone to 1,1,1-trihaloacetone.
O
O
X2
X
NaOH
X
X
Exercise 2:
The following table outlines the three deprotonation reactions when using chlorine as the
halogen atom. Use CAChe to determine the heats of formation for each of the species in the
table, and then derive the enthalpies of reaction for each of the three reactions. Use the “PM3
geometry in water” since the haloform reaction is often done in aqueous solution.
1.
Hf
2.
Hf
O
O
+
______
______
:
H
+
______
H2O
Hrxn
______
______
O
O
Cl
+
______
Cl
OH-
______
O
:
H
+
______
H2O
______
______
O
Cl
3.
+
OH-
Cl
Hf
H
OH-
______
______
Cl
:
Cl
______
+
H2O
______
______
2
Do the enthalpies of reaction show a trend with increasing chlorination? What do these data
suggest about the relative acidity of the three ketones?
Exercise 3:
Fill in the heats of formation on the following tables and calculate the enthalpies of reaction for
the deprotonation reactions for bromine and iodine as well.
Bromine
1.
Hf
2.
Hf
O
O
+
______
______
:
H
+
______
H2O
Hrxn
______
______
O
O
Br
+
______
Br
OH-
______
O
:
H
+
______
H2O
______
______
O
Br
3.
+
OH-
Br
Hf
H
OH-
______
______
Br
:
Br
______
+
H2O
______
______
3
Iodine
1.
Hf
2.
Hf
O
O
+
______
______
:
H
+
______
H2O
Hrxn
______
______
O
O
I
+
______
I
OH-
______
:
H
+
______
H2O
______
______
O
O
I
3.
+
OH-
______
I
:
+
H2O
I
I
Hf
H
OH-
______
______
______
______
Do you observe the same trend for bromine and iodine as you did for chlorine? In general, how
does increasing -halogenation affect the acidity of an -hydrogen on the same carbon?
Using what you have learned in the above exercises, provide an explanation as to why the basepromoted -halogenation reaction is exhaustive.
Part 2: Nucleophilic Acyl Substitution
The second part of the haloform reaction is a nucleophilic acyl substitution
(addition/elimination) reaction. This is the part of the haloform reaction that only works with
methyl ketones. After exhaustive based promoted -halogenation, a methyl ketone is converted
to a trihalomethyl ketone. The trihalomethyl ketone reacts with a hydroxide anion to generate a
carboxylate anion and a haloform molecule. This is the part of the haloform reaction that is
unique to methyl ketones. During the second part of this assignment you will explore why only
trihalomethyl ketones undergo this type of reaction.
4
O
O
O
-
OH
R
R
X2
X
H
-
OH
X
X
R
O
+
X
X
X
Exercise 4:
Draw the mechanism of the reaction of 1,1,1-trihaloacetone with hydroxide anion.
O
O
X
X
X
OH-
H
O
+
X
X
X
Exercise 5:
The first step of a nucleophilic acyl substitution is the attack of the nucleophile.
Draw 1,1,1-trichloroacetone, 1,1-dichloroacetone, 3,3-dichloro-2-butanone, and acetone in
CAChe and optimize their geometries using “PM3 geometry in water”. Then construct the
electrostatic potential on electron density surface using “Current geometry with B88-LYP DFT
wavefunction”. Then find the partial charge at the carbonyl carbon. Fill in the table.
Color of Electron Density
at Carbonyl Carbon
Partial Charge at
Carbonyl Carbon
O
Cl
Cl
Cl
O
Cl
Cl
O
Cl Cl
O
5
Based on the information determined in Exercise 5, which carbonyl compound would be most
susceptible to nucleophilic attack?
Exercise 6:
The second step of a nucleophilic acyl substitution reaction is the loss of the leaving group. This
is usually the rate-determining step. Good leaving groups are often the conjugate bases of strong
acids.
Compare the acidity of methane, chloromethane, dichloromethane, and chloroform. Determine
the enthalpies of reaction for the following acid dissociation reactions, using the PM3 geometry
in water.
1.
Hf
2.
Hf
3.
Hf
4.
Hf
CH4
______
H3CCl
______
H2CCl2
______
HCCl3
______
+
H2O
H3C-
+
______
H2O
______
H2ClC-
+
______
H2O
______
HCl2C-
+
______
H2O
______
Cl3C-
______
______
+
H3O+
Hrxn
+
______
H3O+
______
Hrxn
+
______
H3O+
______
Hrxn
+
______
H3O+
______
Hrxn
______
______
Rank the following four compounds in order of increasing acidity.
CH4
CH3Cl
CH2Cl2
CHCl3
Which of the following four anions is the best leaving group? Explain your choice based on the
data in the table above.
H3C-
H2ClC-
HCl2C-
Cl3C-
6
Exercise 7:
Compare the acidity of chloroform, and 1,1-dichloroethane. Calculate the enthalpies of reaction
for the following reactions using the PM3 geometry in water.
1.
HCCl3
Hf
2.
Hf
______
H3CCHCl2
______
+
H2O
Cl3C:-
+
______
H2O
______
H3CCl2C:-
______
______
+
H3O+
Hrxn
+
______
H3O+
______
Hrxn
______
______
Which of the following tetrahedral intermediates is more likely to kick out the carbanion leaving
group? Explain using the data in the table above.
O
H 3C
HO
O
CCl3
H 3C
HO
CCl2CH3
Based on the exercises you have completed in Part 2, explain why the haloform reaction is
unique to methyl ketones.
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Appendix: Tips for using CAChe for this assignment
Introductory quick tips for using the CAChe Workspace program can be found at:
http://chemed.chem.pitt.edu/cacc/downloads/WS_quick_tips.pdf
More detailed CAChe tutorials can be found, if you are interested, at:
http://chemed.chem.pitt.edu/cacc/CACheTutorial/index.htm
Calculating Heats of Formation
Draw the molecule or ion of interest. The charge of atoms can be changed using the toolbar
immediately above the drawing area.
Beautify the molecule.
Run a new experiment to optimize the geometry. Under “Property of” select Chemical Sample,
and under “Property” select optimized geometry. Since most of the calculations in this
assignment will use the PM3 geometry in water, select this method from the “Using” menu.
Click “Start” to run the experiment. Select “Yes” if asked to save the molecule before the
experiment.
PM3 is a semi-empirical method that is partially based on empirical parameters. It is a good
method for determining optimum geometry of simple organic compounds, and is capable of
calculating qualitatively reliable heats of formation with a relatively short calculation time.
When the experiment is finished, the heat of formation is returned as a line of text in the
Experiment Status window. It should look like the following:
The heat of formation of this molecule is -13.073 kcal/mol.
Constructing an Electrostatic Potential on Electron Density Surface
First, draw, beautify, and optimize the geometry of a molecule or ion as described previously.
Then, run a new experiment. This time select electrostatic potential on electron density as the
“Property”. Select current geometry with B88-LYP DFT wavefunction under the “Using” menu.
Click “Start” to run the experiment. Select “Yes” if asked to save the molecule before the
experiment.
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This calculation uses density functional theory (DFT). The PM3 method is not very good at
examining electron density, but DFT is very good at it. Optimizing a molecule’s geometry using
DFT is a task that takes much longer than optimizing using PM3. However, DFT can calculate
electron density relatively quickly if given a good geometry to start with. This is why we
optimize with PM3 first.
When the calculation is complete, go to the Analyze menu at the top of the window, and select
“Show Surfaces”. Select the XXX.csf.EonD surface (where XXX is the filename), and click
“OK”. The surface will then overlay on top of the molecule.
The surface is color coded by electron density. Warm colors represent areas of less electron
density, and cool colors represent areas of more electron density. In order of increasing electron
density, the colors are:
White<red<yellow<green<sky blue<blue<magenta<purple
Viewing Partial Charges
Partial charges can only be determined after running experiments. Part of running any
experiment involves assigning partial charges to all the atoms. As partial charges have to do with
electron density around an atom, a DFT calculation will give a better partial charge than a PM3
calculation (though any PM3 calculation will generate partial charges).
After running an experiment, select the atom of interest.
Select “Atom Attributes” on the View menu. On the “Label” tab, put a check by “Partial
Charge”. The partial charge label will now appear over the atom of interest.
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