Molecular Modeling
in Undergraduate
Chemistry Education
Warren J. Hehre
Wavefunction, Inc.
18401 Von Karman Ave., Suite 370
Irvine, CA 92612
Alan J. Shusterman
Department of Chemistry
Reed College
3203 S. E. Woodstock Blvd.
Portland, OR 97202
Copyright © 2000 by Wavefunction, Inc.
All rights reserved in all countries. No part of this book
may be reproduced in any form or by any electronic or
mechanical means including information storage and
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publisher, except by a reviewer who may quote brief
passages in a review.
Printed in the United States of America
Preface
Over a little more than a decade, molecular modeling has evolved
from a specialized research tool of limited availability and (presumed)
limited utility, to an important, if not essential, means with which to
explore chemistry. The obvious catalyst has been an explosion in
computer technology. Today’s desktop and laptop computers are as
powerful as yesterdays supercomputers. Computers have become
common fixtures in our lives, and are well on their way to becoming
ubiquitous appliances. Also paramount has been the continued
development of more and more accurate models with which to describe
molecular structure and properties and chemical reactivity. Qualitative
models are rapidly giving way to quantitative treatments. Finally,
computer graphics has made modeling easy to learn and easy to do.
It is inevitable that molecular modeling takes its rightful place in the
teaching of organic chemistry. It offers a natural companion to both
traditional lecture/textbook and laboratory approaches. Modeling not
only facilitates communication of both concepts and content (as do
lectures and textbooks), but also allows discovery of “new chemistry”
(as does a laboratory).
Because molecular models offer an incredibly rich source of visual
and quantitative information, they can be used to great effect to
enhance traditional lectures and classroom discussions. More
important, students can use models in a number of different ways on
their own personal computers to learn and explore chemistry:
Students can study any of the hundreds of molecular models contained
on the CDROM that is included with “The Molecular Modeling
Workbook for Organic Chemistry”1. And, by solving the problems in
the Workbook, they can also learn a great deal of organic chemistry
while simultaneously learning how to work with molecular modeling
data. Two different selections of problems (and associated models)
from the workbook have now been produced as supplements for the
popular organic chemistry textbooks of Wade2 and Bruice3. In
addition, molecular models have now been integrated into the fifth
i
edition of McMurry’s “Organic Chemistry”4 and into the fourth edition
of Carey’s “Organic Chemistry”5.
Students can also use actual molecular modeling programs like PC
SPARTAN Pro and MacSPARTAN Pro6 to learn chemistry in the same
way that a chemist does: by setting up experiments, generating data,
and thinking about its implications. Computational experiments, such
as those contained in “A Laboratory Book of Computational Organic
Chemistry”7, can also serve as a stimulating tool for analyzing
experimental data obtained in the “wet lab”.
These notes are part of a one-day course intended to build a case for
incorporation of molecular modeling in the undergraduate chemistry
curriculum. They first outline the conceptual basis for molecular
modling, and point out obvious similarities and differences between
modeling and experimental approaches to chemistry. Next, they
describe some basic tools for analyzing the results of modeling, with
an emphasis on graphical tools.
Warren J. Hehre
Wavefunction, Inc.,
18401 Von Karman Avenue
Suite 370
Irvine, CA 92612
Alan J. Shusterman
Department of Chemistry
Reed College
3203 S. E. Woodstock Blvd.
Portland, OR 97202
1. W.J. Hehre, A.J. Shusterman and J.E. Nelson, The Molecular Modeling Workbook
for Organic Chemistry, Wavefunction, Irvine, CA, 1998.
2. W.J. Hehre, A.J. Shusterman and J.E. Nelson, Molecular Modeling Workbook to
Wade’s Organic Chemistry, Prentice Hall, Upper Saddle River, NJ/Wavefunction,
Irvine, CA, 2000.
3. W.J. Hehre, A.J. Shusterman and J.E. Nelson, Molecular Modeling Workbook
for Bruice’s Organic Chemistry, Prentice Hall, Upper Saddle River, NJ/
Wavefunction, Irvine, CA, 2000.
4. J. McMurry, Organic Chemistry, fifth edition, Brooks/Cole, Pacific Grove, CA,
2000.
5. F.A. Carey, Organic Chemistry, fourth edition, McGraw Hill, New York, 2000.
6. PC SPARTAN Pro and MacSPARTAN Pro are products of Wavefunction.
7. W.J. Hehre, A.J. Shusterman and W.W. Huang, A Laboratory Book of
Computational Organic Chemistry, Wavefunction, Irvine, CA, 1996, 1998.
ii
Table of Contents
INTRODUCTION ........................................................................ 1
MOLECULAR MODELS ........................................................... 5
Electron Density Models ........................................................... 6
Electrostatic Potential Models ................................................... 9
Electrostatic Potential Maps .................................................... 10
Molecular Orbital Models ....................................................... 13
Models that Move .................................................................... 17
CONCEPTUAL BACKGROUND ............................................ 19
Potential Energy Surfaces........................................................ 20
Molecular Mechanics .............................................................. 24
Quantum Mechanics ................................................................ 25
MOLECULAR MODELING IN LECTURE .......................... 27
Visualizing Chemical Bonds ................................................... 29
The SN2 Reaction ..................................................................... 31
Flexible Molecules .................................................................. 36
Intermolecular Interactions ...................................................... 39
MOLECULAR MODELING FOR STUDENTS..................... 43
The Molecular Modeling Workbook for Organic Chemistry .. 45
Molecular Modeling Supplements to Wade and Bruice
Organic Chemistry Texts ...................................................... 48
McMurry and Carey Organic Chemistry Texts ....................... 49
MOLECULAR MODELING IN THE LABORATORY ........ 53
Is Thiophene Aromatic ............................................................ 56
Thermodynamic vs. Kinetic Control ....................................... 58
Molecular Recognition. Hydrogen-Bonded Base Pairs........... 60
PROPER ROLE OF MOLECULAR MODELING ................ 63
iii
Introduction
Molecular Modeling
vs. Experiment
experiment
molecular modeling
define problem
design experimental
procedure and build
apparatus
specify and build
appropriate models
do experiment
do calculations
analyze results
Why Should We Use
Molecular Modeling
to Teach Chemistry?
•
Models allow students to “think like a molecule”.
Students “see” what a molecule sees and “feel”
what a molecule feels. Models provide a window
on the molecular world.
•
We already use a variety of crude models to teach
chemistry . . . Lewis structures, resonance, Hückel
theory. Computer models provide a more realistic
account of molecular structure and chemistry.
•
Models are easy to use, inexpensive and safe.
Models are student-friendly educational tools.
They are not just for “experts”.
Should molecular modeling
replace experimental
chemistry?
Of course not!
The goals of chemistry are not changed by molecular
modeling. On a practical level, students need to learn
how to make things (synthesis) and how to figure out
what these things are (analysis). On an intellectual
level, they need to understand the “rules” that describe
chemical behavior.
Molecular modeling is a tool for achieving these goals.
Synthesis and analysis are experimental. They cannot
(and should not) be done away with. However,
modeling does change the way we do syntheses and
analysis. And, it speaks directly to the intellectual goals
of chemistry.
A modern chemical education requires practical
training both in experimentation and in modeling.
Molecular Models
Electron Density Models
Electron density models show the locations of
electrons. Large values of the density will first reveal
atomic positions (the X-ray diffraction experiment)
and then chemical bonds, while even smaller values
will indicate overall molecular size.
large density value
small density value
To Bond or Not to Bond
Unlike conventional structure models which require
bonds to be drawn explicitely, electron density models
may be used to elucidate bonding. For example, the
electron density model for diborane shows that the
borons are not bonded.
This allows the appropriate Lewis structure to be
drawn.
not
Are All Partial Bonds
the Same?
Electron density models may be used to describe
reaction transition states in which bonds may be
partially formed or broken. For example, the electron
density model for the transition state for pyrolysis of
ethyl formate, leading to formic acid and ethene,
H
C O
O
H
H
H
H
C
C
C O
C O
H
H
H
ethyl formate
∆
O
H C
H
H
C H
H
O
H
H C
formic acid
H
H
C H ethene
clearly distinguishes between the partial CO bond,
which is nearly fully broken, and the partial bonds
involving the migrating hydrogen both of which are
substantial.
The conventional picture suggests that all partial bonds
are the same.
Electrostatic Potential Models
The electrostatic potential is the energy of interaction
of a point positive charge (an electrophile) with the
nuclei and electrons of a molecule. Negative
electrostatic potentials indicate areas that are prone to
electrophilic attack. For example, a negative
electrostatic potential of benzene shows that
electrophilic attack should occur onto the π system,
while the corresponding electrostatic potential for
pyridine shows that an electrophile should attack the
nitrogen in the σ plane.
benzene
pyridine
The “electrophilic chemistry” of these two seemingly
similar molecules is very different.
Electrostatic Potential Maps
The electrostatic potential can be mapped onto the
electron density by using color to represent the value
of the potential. The resulting model simultaneously
displays molecular size and shape and electrostatic
potential value. Colors toward “red” indicate negative
values of the electrostatic potential, while colors
toward “blue” indicate positive values of the potential.
electron density
+
electrostatic
potential map
electrostatic potential
Are Resonance Structures
Always Completely Truthful?
The two resonance structures for the zwitterion form
of β-alanine show positive charge on nitrogen and
negative charge distributed equally onto the two
oxygens.
O–
O
H3N+CH2CH2C
O–
H3N+CH2CH2C
O
This is reflected in the electrostatic potential map
which clearly shows that the ammonium group is
positive (blue) and that the carboxylate group is
negative (red).
Closer inspection reveals, however, that it is not the
nitrogen which bears the brunt of the positive charge,
but rather the attached hydrogens.
Why is More, Better?
Four resonance structures may be drawn for planar
benzyl cation, but only one may be drawn if the
carbocation center is twisted out of plane.
+
+
+
+
+
Why does this necessarily imply that benzyl cation
wants to be planar?
Electrostatic potential maps show charge separation
for twisted benzyl cation, but almost no separation
for the planar cation.
planar
twisted
Coulomb’s law (“separation of charge requires
energy”) is responsible for the preference.
Molecular Orbital Models
Molecular orbitals are the solutions of the approximate
quantum mechanical equations of electron motion.
They are made up of sums and differences of atomic
solutions (atomic orbitals), just like molecules are
made up of combinations of atoms.
Molecular orbitals for very simple molecules are often
interpreted in terms of familiar chemical bonds, for
example, in acetylene.
σ
π
π
This can be deceptive. While the two π molecular
orbitals, like the two π bonds in acetylene, involve
only the two carbons, the σ molecular orbital is a
combination of CC and CH σ bonds.
Molecular Orbital Models
Sometimes unoccupied molecular orbitals provide
important chemical insight. The lowest-unoccupied
molecular orbital (the LUMO), in particular, demarks
the location of positive charge in a molecule. For
example, the LUMO in planar benzyl cation is spread
out over four different carbons while the corresponding
molecular orbital in perpendicular benzyl cation
resides primarily on only one carbon.
planar benzyl
cation
perpendicular benzyl
cation
This is the same result provided by resonance theory.
H
+
H
H
H
H
H
H
H
H
H
+
+
+
+
Nucleophilic Addition
to Enones
The LUMO of cyclohexenone is primarily
concentrated on the carbonyl carbon and on the β
carbon. This is most clearly shown by mapping the
LUMO onto an electron density model. Areas which
have the greatest affinity for a nucleophilic are colored
“blue”.
Both carbonyl chemistry and Michael addition
chemistry are easily anticipated.
O
O
H
Nu
HO
Nu
Nu
Nu
Michael addition
carbonyl
Why Bother . . .
with a computer when conventional models can easily
be constructed with a pencil?
The computer is the pencil of this generation. It’s use
is no less familiar than that of the pencil, and molecular
models . . . electron densities, electrostatic potentials,
molecular orbitals . . . follow from an essentially
correct picture of molecular structure. They are both
more general and more quantitative than the
qualitative arguments in widespread use, and can be
used to explore new chemistry.
Models that Move
Models need not be limited to static pictures. An
animation is the best way to show atomic motions in
vibrating molecules. While other methods might be
used for simple molecules such as water,
H
O
H
H
O
H
H
O
H
there really is no alternative for complex systems.
Models that Move
Animations also allow the motions of atoms during a
chemical reaction to be shown. For example,
animation of the reaction coordinate for the pyrolysis
of ethyl formate shows the simultaneous transfer of
the hydrogen atom to the carbonyl oxygen along with
carbon-oxygen bond cleavage.
H
H
C O
O
H
C O
H
C
C
H
H
H
H
ethyl formate
∆
O
H C
H
C O
H
C H
H
O
H
H C
formic acid
H
H
C H ethene
Electron density models and electrostatic potential
maps (in addition to structure displays) may also be
animated, showing electron motion.
Conceptual
Background
Potential Energy Surfaces
A potential energy surface is a plot of energy vs.
reaction coordinate. It connects reactants to products
via a transition state.
transition state structure
transition state
energy
reactants
products
equilibrium structures
reaction coordinate
Energy minima correspond to equilibrium structures.
The energy maximum corresponds to a transition
state structure.
Potential Energy Surfaces
transition state
"kinetics"
energy
reactants
"thermodynamics"
products
reaction coordinate
The relative energies of equilibrium structures give
the relative stabilities of the reactants and products
(thermodynamics).
The energy of the transition state relative to reactants
gives information about the rate of reaction (kinetics).
Potential Energy Surfaces
A reaction pathway may comprise several steps and
involve several different transition states and reactive
intermediates. The rate limiting step in the overall
pathway is that which passes over the highest-energy
transition state.
transition state
transition state
energy
reactants
intermediate
reaction coordinate
rate limiting
step
products
The pathway with the lowest energy rate limiting step
is the reaction mechanism.
Potential Energy Surfaces
Molecular modeling is primarily a tool for calculating
the energy of a given molecular structure. Thus, the
first step in designing a molecular modeling
investigation is to define the problem as one involving
a structure-energy relationship.
There are two conceptually different ways of thinking
about energy.
Molecular Mechanics
A “Chemist’s” Model
Molecular mechanics describes the energy of a
molecule in terms of a simple function which accounts
for distortion from “ideal” bond distances and angles,
as well as and for nonbonded van der Waals and
Coulombic interactions.
van der Waals interaction
distance
distortion
angle
distortion
dihedral
distortion
δ+
Coulombic
interaction
δ-
Quantum Mechanics
A “Physicist’s” Model
Quantum mechanics describes the energy of a
molecule in terms of interactions among nuclei and
electrons. This is given by the Schrödinger equation,
which may be solved exactly for the hydrogen atom.
potential energy
total energy
-h
8π2m
∆
2
2
+ V(x,y,z)
kinetic energy
ψ(x,y,z) = E ψ(x,y,z)
wavefunction describing
the system
The wavefunctions of the hydrogen atom are the
familar s, p, d … atomic orbitals.
s
p
d
The square of the wavefunction gives the probability
of finding an electron. This is the electron density,
and may be obtained from X-ray diffraction.
Too Good to be True
While the Schrödinger equation is easy to write down
for many-electron atoms and molecules, it is
impossible to solve. Approximations are needed.
Schrödinger Equation HΨ = EΨ
assume that nuclei
don’t move
“Born-Oppenheimer
Approximation”
separate electron motions
“Hartree-Fock
Approximation”
get electron motion in
molecules by combining
electron motion in atoms
“LCAO Approximation”
Practical Molecular Orbital Methods
Molecular Modeling
in Lecture
Molecular Modeling in Lecture
Molecular models can be introduced into almost any
chemistry lecture. They not only liven the discussion
with “pretty pictures”, but more importantly encourage
students to see and think for themselves. They free
teachers from the “limits of the chalkboard” and allow
examination and discussion of “real” molecules.
Visualizing Chemical Bonds
Are the different kinds of chemical bonds to which
chemists refer (nonpolar covalent, polar covalent and
ionic) fundamentally different? Look at electron
density models for hydrogen fluoride, hydrogen and
lithium hydride.
H-H
H-F
H-Li
The size of the electron density surface indicates the
size of the electron cloud. As expected, the size of the
cloud surrounding hydrogen is smallest in hydrogen
fluoride and largest in lithium hydride. Note, however,
that in all three molecules the electrons are shared,
although not equally. The bonds in all three molecules
are best described as covalent, although they differ in
their polarity.
Visualizing Chemical Bonds
An even clearer picture comes from electrostatic
potential maps, where the color red demarks regions
with excess negative charge and the color blue
demarks regions with excess positive charge.
H-H
H-F
H-Li
Hydrogen fluoride and lithium hydride look very
similar, except that the hydrogen in the former is
positively charged while the hydrogen in the latter is
negatively charged.
The SN2 Reaction
N C–
CH3 I
N C CH3 + I –
An animation of the familiar SN2 reaction clearly
shows the inversion at carbon, but there are other
important questions.
The SN2 Reaction
Why does cyanide attack from carbon and not
nitrogen? Doesn’t this contradict the fact that nitrogen
is more electronegative than carbon?
Molecular orbital models provide insight. Look at the
highest-occupied molecular orbital of cyanide. This
is where the “most available” electrons reside.
N≡C
It is actually concentrated on both carbon and nitrogen,
meaning that two different SN2 products are possible.
However, it is more heavily concentrated on carbon,
meaning that acetonitrile will be the dominant product.
The SN2 Reaction
Why does iodide leave following attack by cyanide?
Again, molecular orbital models provide insight. Look
at the lowest-unoccupied molecular orbital of methyl
iodide. This is where the electrons will go.
It is antibonding between carbon and iodine meaning
that the CI bond will cleave during attack.
The SN2 Reaction
We tell students that bromide reacts faster with methyl
bromide than with tert-butyl bromide because of
increased crowding in the transition state of the
tert-butyl system. This is not true. Space-filling models
of the two transition states show both to be uncrowded.
What is true is that the carbon-bromine distance in
the transition state in the tert-butyl system is larger
than that in the methyl system.
2.5Å
2.9Å
The SN2 Reaction
This leads to an increase in charge separation as clearly
shown by electrostatic potential maps for the two
transition states.
This and not steric crowding is the cause of the
decrease in reaction rate.
Flexible Molecules
Interconversion of anti and gauche forms of n-butane
is readily visualized as a smooth rotation about the
central CC bond.
We tell (show) students that all bonds are “staggered”
in these structures.
Diaxial and diequatorial forms of trans-1,2-dimethylcyclohexane are very closely related to anti and
gauche forms of n-butane.
diaxial
diequatorial
We tell students that here too all bonds are staggered.
Flexible Molecules
What we fail to convey is that the cyclohexane ring
undergoes the same type of conformational change
as n-butane. That is, it undergoes smooth rotation. The
difficulty for the lecturer is that this change is not easily
portrayed by manipulating physical models. This
obstacle is readily overcome with molecular models.
Note in particular:
i) The motion is smooth, just as it is in n-butane. It
doesn’t “jump” as suggested by manipulating
physical models.
ii) The motion corresponds to bond rotation, just as
it does in n-butane.
Flexible Molecules
iii) The motion appears to occur in two distinct steps.
One end of the ring seems to move first and then
the other end seems to move. This corresponds
closely to the usual (and very confusing) energy
diagram found in virtually all organic textbooks.
transition state
(eclipsed)
transition state
(eclipsed)
energy
diaxial
(staggered)
twist-boat
(staggered)
diequatorial
(staggered)
reaction coordinate
There is an intermediate (twist boat) and it too is
staggered. The two transition states involve
eclipsing interactions.
Intermolecular Interactions
Acetic acid is known to form a stable hydrogenbonded dimer. What is it’s structure?
O
H3C
O
C
O
H
O
H3C
H
C
O
CH3
H3C
O
C
H
O
C
O
C
O
O
H
CH3
H
O
O C
CH3
Look at an electrostatic potential map for acetic acid.
Which atom is positively charged and most likely to
act as a hydrogen-bond donor?
Which atom is most negatively charged and most
likely to act as a hydrogen-bond acceptor?
Intermolecular Interactions
Apply this same tool to a related question where you
don’t know the answer (or where you “know” the
wrong answer).
What is the crystal structure of benzene?
:
:
or
:
stacked
:
perpendicular
Intermolecular Interactions
Look at the electrostatic potential map for benzene.
The center (π system) is electron rich while the
periphery (σ system) is electron poor. Stacking the
rings results in unfavorable Coulombic interactions,
while a perpendicular arrangement of benzene rings
results in favorable Coulombic interactions between
π and σ systems.
Intermolecular Interactions
The X-ray structure of crystalline benzene shows a
perpendicular arragement!
Molecular Modeling
for Students
Molecular Modeling in the
Curriculum
“Doing chemistry” with molecular modeling is a mulistep progress...not so different from doing
experimental chemistry.
Define Problem
Build Models
Do Calculations
Analyze Results
Given a “full” curriculum, the question that needs to
be answered is how much of this process to turn over
to students.
One approach is to leave only the analysis of the
modeling results (and learning the chemistry that
follows from these results) to the student. The
advantage of this approach is that it requires the fewest
resources (hardware and software support, student
training), while guaranteeing high quality models and
maximum student-model interaction.
The Molecular Modeling
Workbook for
ORGANIC CHEMISTRY
A collection of over 200 problems arranged by
chapters that parallel the contents of your organic
chemistry textbook.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Lewis Structures and Resonance Theory
Acids and Bases
Reaction Pathways and Mechanisms
Stereochemistry
Alkanes and Cycloalkanes
Nucleophilic Substitution and Elimination
Alkenes and Alkynes
Alcohols and Ethers
Ketones and Aldehydes. Nucleophilic Addition
Carboxylic Acid Derivatives. Nucleophilic Substitution
Enolates and Nucleophiles
Conjugated Polyenes and Aromaticity
Electrophilic and Nucleophilic Aromatic Substitution
Nitrogen-Containing Compunds
Heterocycles
Biological Chemistry
Free Radicals and Carbenes
Polymers
Spectroscopy
Mass Spectrometry
Pericyclic Reactions
The Molecular Modeling
Workbook for
ORGANIC CHEMISTRY
Problems in each chapter address essential topics.
Chapter 11 Enolates and Nucleophiles
1
2
3
4
5
6
7
8
9
10
11
12
13
Keto/Enol Tautomerism
H/D Exchange Reactions
What Makes a Good Enolate?
Enolate Acidity, Stability and Geometry
Kinetic Enolates
Real Enolates
Enolates, Enols and Enamines
Enolates are Ambident Nucleophiles
Silylation and Enolates
Stereochemistry of Enolate Alkylation
Enolate Dianions
Aldol Condensation
Dieckmann Condensation
The Molecular Modeling
Workbook for
ORGANIC CHEMISTRY
Each problem uses one or more models, and students
are required to look at and query these models to solve
the problem. The models are contained on a CD-ROM
that comes with the workbook, and can be viewed on
a Mac or PC.
All models provide many types of information
obtained from molecular orbital calculations,
including structure, energy and atomic charges. Many
models also provide molecular orbitals, electron
density surfaces and electrostatic potential maps
among other graphical displays.
Models include many types of molecular species,
including conformers, reactive intermediates,
transition states and weak complexes. A number of
models involve sequences that can be animated.
Molecular Modeling
Supplements to
Wade and Bruice
Organic Chemistry Texts
Collections of problems drawn from “The Molecular
Modeling Workbook for Organic Chemistry” and
keyed to the Wade and Bruice Organic Chemistry
texts, respectively.
McMurry and Carey Organic
Chemistry Texts
•
Extensive use of molecular models in text and
access to models from SPARTANView
*
*
From J. McMurry, Organic Chemistry, fifth edition, Brooks/Cole,Pacific
Grove, CA, 2000.
McMurry and Carey Organic
Chemistry Texts
•
End-of-chapter molecular modeling problems
requiring use of SPARTANView or SPARTANBuild
*
*
From J. McMurry, Organic Chemistry, fifth edition, Brooks/Cole,Pacific
Grove, CA, 2000.
McMurry and Carey Organic
Chemistry Texts
•
Essays describing molecular models and tutorials
illustrating their use
*
*
From F.A. Carey, Organic Chemistry, fourth edition, McGraw-Hill,
Columbus, OH, 2000.
. . . Bringing Molecular
Modeling to Students
•
Tutorial for SPARTANBuild . . . an electronic model
kit
*
*
From F.A. Carey, Organic Chemistry, fourth edition, McGraw-Hill,
Columbus, OH, 2000.
Molecular Modeling
in the Laboratory
A Laboratory Approach to
Molecular Modeling
Student problems based on precalculated molecular
models or lecture demonstrations using molecular
models provide an incomplete picture. A “laboratory”
approach in which students build their own models,
do whatever calculations may be required and then
analyze their findings (just like in an experimental
organic laboratory) offers both students and teachers
much greater flexibility. Because it puts students
directly in contact with actual molecular modeling
software, it teaches them that calculations, like
experiments, are not instantaneous, and that good
“experimental design” is important.
A Laboratory Book of
Computational Organic
Chemistry1
This comprises a collection of 80+ “organic
experiments”, much like the experiments found in a
conventional organic laboratory book. They cover a
variety of topics and range of difficulty. The common
feature is that they are “hands-on” and require students
to use PC SPARTAN Pro or MacSPARTAN Pro. . . just
like “real” experiments require hands-on use of
glassware.
1. W.J. Hehre, A.J. Shusterman and W.W. Huang, A Laboratory
Book of Computational Organic Chemistry, Wavefunction,
Irvine, CA, 1996, 1998.
Is Thiophene Aromatic?
elementary
advanced
Objective:
To quantify the “aromaticity” of thiophene.
Background:
Hydrogenation of benzene to 1,3-cyclohexadiene is
endothermic, whereas the corresponding reactions
taking 1,3-cyclohexadiene to cyclohexene and then
to cyclohexane, are both exothermic.
+ H2
+ H2
DH = 6 kcal/mol
DH = -26 kcal/mol
+ H2
DH = -28 kcal/mol
The difference is due to aromaticity. Addition of H2
to benzene “trades” an H-H bond and a C-C π bond
for two C-H bonds, but in so doing destroys the
aromaticity of benzene, whereas addition to either
cyclohexadiene or cyclohexene “trades” the same
bonds but does not result in any loss of aromaticity.
Therefore, the difference in the heats of hydrogenation
(≈33 kcal/mol) corresponds to the aromatic
stabilization of benzene.
Is Thiophene Aromatic?
Procedure:
Calculate the energetics of hydrogen addition to
thiophene and to the intermediate dihydrothiophene.
S
+ H2
S
+ H2
S
The difference provides a measure of the aromaticity
of thiophene.
Question:
Is thiophene as aromatic as benzene? Half as aromatic?
Extensions:
Ask the same question about any molecule you like.
Thermodynamic vs.
Kinetic Control
elementary
advanced
Objective:
To understand the difference between “thermodynamic”
and “kinetic” reaction products.
Background:
Cyclization of hex-5-enyl radical can either yield
cyclopentylmethyl radical or cyclohexyl radical.
or
While the latter might be expected (it should be less
strained, and 2° radicals are generally more stable than
1° radicals), the opposite is normally observed, e.g.,
Bu3 SnH
AIBN
Br
∆
+
17%
+
81%
2%
Thermodynamic vs.
Kinetic Control
Procedure (part A):
Calculate the energies of both cyclopentylmethyl and
cyclohexyl radicals.
Question (part A):
What is the thermodynamic product of ring closure?
What would be the ratio of major to minor products
at room temperature assuming that the reaction is
under thermodynamic control? (Use the Boltzmann
equation.)
Procedure (part B):
Locate transition states for cyclization reactions
leading to cyclopentylmethyl and cyclohexyl radicals,
and obtain their energies.
Questions (part B):
What is the kinetic product of ring closure? What
would be the ratio or major to minor products at room
temperature assuming that the reaction is under kinetic
control? (Use the Eyring equation.) Is the cyclization
reaction under thermodynamic or kinetic control or is
it not possible to tell? Elaborate.
Molecular Recognition.
Hydrogen-Bonded Base Pairs
elementary
advanced
Objective:
To model hydrogen-bonding between DNA base pairs
in terms of charge-charge interactions. To identify
nucleotide mimics.
Background:
The genetic code is “read” through the selective
formation of hydrogen-bonded complexes, or WatsonCrick base pairs, of adenine (A) and thymine (T)
(forms A-T base pair), and guanine (G) and cytosine
(C) (forms G-C base pair). The importance of this
hydrogen bond-based code lies in the fact that virtually
all aspects of cell function are regulated by proper
base pair formation, and many diseases can be traced
to “reading” errors, i.e., the formation of incorrect base
pairs.
Molecular Recognition.
Hydrogen-Bonded Base Pairs
Procedure (part A):
Calculate electrostatic potential maps for:
HN
O
NH 2
O
NCH3
O
N
N
N
N
CH 3
CH3
1-methylthymine
(MeT)
9-methyladenine
(MeA)
N
O
NCH3
H2N
1-methylcytosine
(MeC)
N
HN
H2N
N
N
CH 3
9-methylguanine
(MeG)
Identify electron-rich and electron-poor sites that
would be suitable for hydrogen bonding. Draw all base
pairs that involve two or three hydrogen bonds.
Choose one naturally occuring base pair and one that
does not occur naturally (maintain the number of
hydrogen bonds). Obtain geometries and energies for
both, and calculate the total hydrogen bond energy in
each.
Questions (part A):
What is the magnitude of the hydrogen-bond energy
for in the naturally occuring system? Is it as strong as
a normal chemical bond? What is it in the system
which does not occur naturally? What is the difference?
Molecular Recognition.
Hydrogen-Bonded Base Pairs
Procedure (part B):
Calculate electrostatic potential maps for AP and NA,
heterocyclic molecules that mimic the hydrogen
bonding properties of DNA nucleotides.
O
HN
H2N
6-amino-2-pyridone
(AP)
O
N
N
N
H
N-naphtharidinyl acetamide
(NA)
Identify electron-rich and electron-poor sites for each,
and examine the possible hydrogen bonded pairs
involving AP or NA and one of the natural bases. Pick
your best candidate, obtain a geometry and energy
for the hydrogen-bonded complex and calculate the
hydrogen-bonded energy.
Question (part B):
Is the magnitude of the hydrogen-bonding interaction
in your mimic as large as in a natural base pair?
Proper Role of
Molecular Modeling
Focus on Chemistry
Modeling is a tool for doing chemistry. Molecular
modeling is best treated in the same way as NMR - as
a tool, not a goal. A good model has the same value as
a good NMR spectrum. Molecular modeling allows
you to “do” and teach chemistry better by providing
better tools for investigating, interpreting, explaining,
and discovering new phenomena.
Don’t be Afraid
Modeling is accessible. Anyone can build a useful
model.
Modeling is “hands on”. Molecular modeling, like
experimental chemistry is a “laboratory” science, and
must be learned by “doing” and not just reading.
Modeling does not need to be intimidating. The
underpinnings of molecular modeling (quantum
mechanics) are certainly intimidating to many
chemists, but so too are the underpinnings of NMR.
Using molecular modeling should be no more
intimidating than obtaining an NMR spectrum.
Modeling is not difficult to learn and do. Molecular
modeling is easy to do given currently available
software (probably easier than taking an NMR
spectrum). The difficulty lies in asking the right
questions of the models and properly interpreting what
comes out of them.