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 retrieval systems without permission in writing from the 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. Todays 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 Chemistry1. 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
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edition of McMurrys Organic Chemistry4 and into the fourth edition of Careys Organic Chemistry5. 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 Chemistry7, 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 Wades 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 Bruices 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.

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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

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Introduction

Molecular Modeling vs. Experiment

experiment
define problem design experimental procedure and build apparatus

molecular modeling

specify and build appropriate models

do experiment analyze results

do calculations

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, Hckel 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 C C H O H C O H C H C H H H O H H C H C O H H C H ethene formic acid

H H H ethyl formate

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 system, while the corresponding electrostatic potential for pyridine shows that an electrophile should attack the nitrogen in the 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 -alanine show positive charge on nitrogen and negative charge distributed equally onto the two oxygens.
O H3N+CH2CH2C O H3N+CH2CH2C O 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

Coulombs 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.

This can be deceptive. While the two molecular orbitals, like the two bonds in acetylene, involve only the two carbons, the molecular orbital is a combination of CC and CH 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 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 H Nu Michael addition carbonyl Nu O Nu HO Nu

Why Bother . . .
with a computer when conventional models can easily be constructed with a pencil? The computer is the pencil of this generation. Its 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 C O O H C C H

H C O O H C H C H H H

H C O O H H C H H C H ethene formic acid

H H H ethyl formate

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

rate limiting step

reaction coordinate

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 Chemists 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 dihedral distortion

+ Coulombic interaction -

angle distortion

Quantum Mechanics A Physicists Model

Quantum mechanics describes the energy of a molecule in terms of interactions among nuclei and electrons. This is given by the Schrdinger equation, which may be solved exactly for the hydrogen atom.
potential energy total energy -h 82m
2 2

+ V(x,y,z)

(x,y,z) = E (x,y,z)

kinetic energy

wavefunction describing the system

The wavefunctions of the hydrogen atom are the familar s, p, d atomic orbitals.

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 Schrdinger equation is easy to write down for many-electron atoms and molecules, it is impossible to solve. Approximations are needed.
Schrdinger Equation H = E assume that nuclei dont move separate electron motions Born-Oppenheimer Approximation 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? Doesnt 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.

NC

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.
2.5 2.9

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 doesnt 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 its structure?
O H3C C O H H3C H O C O CH3 C O H O O H O C CH3 H O C CH3 O H3C O C O

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 dont 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 ( system) is electron rich while the periphery ( 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 and 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 DH = 6 kcal/mol + H2 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 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:
O HN O CH3 1-methylthymine (MeT) NCH3 N N NH 2 N N CH 3 9-methyladenine (MeA) H2N 1-methylcytosine (MeC) N O NCH3 H2N HN N O 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) N N N H O

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.

Dont 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.