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Molecular Modelingin Undergraduate
Chemistry Education
Warren J. HehreWavefunction, Inc.
18401 Von Karman Ave., Suite 370Irvine, CA 92612
Alan J. ShustermanDepartment of Chemistry
Reed College3203 S. E. Woodstock Blvd.
Portland, OR 97202
Copyright © 2000 by Wavefunction, Inc.
All rights reserved in all countries. No part of this bookmay be reproduced in any form or by any electronic ormechanical means including information storage andretrieval systems without permission in writing from thepublisher, except by a reviewer who may quote briefpassages in a review.
Printed in the United States of America
PrefaceOver a little more than a decade, molecular modeling has evolvedfrom a specialized research tool of limited availability and (presumed)limited utility, to an important, if not essential, means with which toexplore chemistry. The obvious catalyst has been an explosion incomputer technology. Today’s desktop and laptop computers are aspowerful as yesterdays supercomputers. Computers have becomecommon fixtures in our lives, and are well on their way to becomingubiquitous appliances. Also paramount has been the continueddevelopment of more and more accurate models with which to describemolecular structure and properties and chemical reactivity. Qualitativemodels 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 theteaching of organic chemistry. It offers a natural companion to bothtraditional lecture/textbook and laboratory approaches. Modeling notonly facilitates communication of both concepts and content (as dolectures and textbooks), but also allows discovery of “new chemistry”(as does a laboratory).
Because molecular models offer an incredibly rich source of visualand quantitative information, they can be used to great effect toenhance traditional lectures and classroom discussions. Moreimportant, students can use models in a number of different ways ontheir own personal computers to learn and explore chemistry:
Students can study any of the hundreds of molecular models containedon the CDROM that is included with “The Molecular ModelingWorkbook for Organic Chemistry”1. And, by solving the problems inthe Workbook, they can also learn a great deal of organic chemistrywhile simultaneously learning how to work with molecular modelingdata. Two different selections of problems (and associated models)from the workbook have now been produced as supplements for thepopular organic chemistry textbooks of Wade2 and Bruice3. Inaddition, molecular models have now been integrated into the fifth
i
edition of McMurry’s “Organic Chemistry”4 and into the fourth editionof Carey’s “Organic Chemistry”5.
Students can also use actual molecular modeling programs like PCSPARTAN Pro and MacSPARTAN Pro6 to learn chemistry in the sameway that a chemist does: by setting up experiments, generating data,and thinking about its implications. Computational experiments, suchas those contained in “A Laboratory Book of Computational OrganicChemistry”7, can also serve as a stimulating tool for analyzingexperimental data obtained in the “wet lab”.
These notes are part of a one-day course intended to build a case forincorporation of molecular modeling in the undergraduate chemistrycurriculum. They first outline the conceptual basis for molecularmodling, and point out obvious similarities and differences betweenmodeling and experimental approaches to chemistry. Next, theydescribe some basic tools for analyzing the results of modeling, withan emphasis on graphical tools.
Warren J. Hehre Alan J. Shusterman Wavefunction, Inc., Department of Chemistry 18401 Von Karman Avenue Reed College Suite 370 3203 S. E. Woodstock Blvd. Irvine, CA 92612 Portland, OR 97202
1. W.J. Hehre, A.J. Shusterman and J.E. Nelson, The Molecular Modeling Workbookfor Organic Chemistry, Wavefunction, Irvine, CA, 1998.
2. W.J. Hehre, A.J. Shusterman and J.E. Nelson, Molecular Modeling Workbook toWade’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 Workbookfor 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 ........................................................... 5Electron Density Models ........................................................... 6Electrostatic Potential Models ................................................... 9Electrostatic Potential Maps .................................................... 10Molecular Orbital Models ....................................................... 13Models that Move .................................................................... 17
CONCEPTUAL BACKGROUND ............................................ 19Potential Energy Surfaces........................................................ 20Molecular Mechanics .............................................................. 24Quantum Mechanics ................................................................ 25
MOLECULAR MODELING IN LECTURE .......................... 27Visualizing Chemical Bonds ................................................... 29The SN2 Reaction ..................................................................... 31Flexible Molecules .................................................................. 36Intermolecular Interactions...................................................... 39
MOLECULAR MODELING FOR STUDENTS..................... 43The Molecular Modeling Workbook for Organic Chemistry .. 45Molecular Modeling Supplements to Wade and Bruice Organic Chemistry Texts ...................................................... 48McMurry and Carey Organic Chemistry Texts ....................... 49
MOLECULAR MODELING IN THE LABORATORY ........ 53Is Thiophene Aromatic ............................................................ 56Thermodynamic vs. Kinetic Control ....................................... 58Molecular Recognition. Hydrogen-Bonded Base Pairs........... 60
PROPER ROLE OF MOLECULAR MODELING ................ 63
iii
Introduction
Molecular Modelingvs. Experiment
experiment molecular modeling
specify and buildappropriate models
define problem
design experimentalprocedure and build
apparatus
do experiment do calculations
analyze results
Why Should We UseMolecular Modelingto 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 windowon the molecular world.
• We already use a variety of crude models to teachchemistry . . . Lewis structures, resonance, Hückeltheory. Computer models provide a more realisticaccount 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 modelingreplace experimental
chemistry?
Of course not!
The goals of chemistry are not changed by molecularmodeling. On a practical level, students need to learnhow to make things (synthesis) and how to figure outwhat these things are (analysis). On an intellectuallevel, they need to understand the “rules” that describechemical 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 andanalysis. And, it speaks directly to the intellectual goalsof chemistry.
A modern chemical education requires practicaltraining both in experimentation and in modeling.
Molecular Models
Electron Density Models
Electron density models show the locations ofelectrons. Large values of the density will first revealatomic positions (the X-ray diffraction experiment)and then chemical bonds, while even smaller valueswill indicate overall molecular size.
large density value
small density value
To Bond or Not to Bond
Unlike conventional structure models which requirebonds to be drawn explicitely, electron density modelsmay be used to elucidate bonding. For example, theelectron density model for diborane shows that theborons are not bonded.
This allows the appropriate Lewis structure to bedrawn.
not
Are All Partial Bondsthe Same?
Electron density models may be used to describereaction transition states in which bonds may bepartially formed or broken. For example, the electrondensity model for the transition state for pyrolysis ofethyl formate, leading to formic acid and ethene,
OC C
HOC
H
HH HH
ethyl formate
∆formic acid
ethene
O
C C
OCH
H
H HH H
OC C
HOC
H
HH H
H
clearly distinguishes between the partial CO bond,which is nearly fully broken, and the partial bondsinvolving the migrating hydrogen both of which aresubstantial.
The conventional picture suggests that all partial bondsare the same.
Electrostatic Potential Models
The electrostatic potential is the energy of interactionof a point positive charge (an electrophile) with thenuclei and electrons of a molecule. Negativeelectrostatic potentials indicate areas that are prone toelectrophilic attack. For example, a negativeelectrostatic potential of benzene shows thatelectrophilic attack should occur onto the π system,while the corresponding electrostatic potential forpyridine shows that an electrophile should attack thenitrogen in the σ plane.
benzene pyridine
The “electrophilic chemistry” of these two seeminglysimilar molecules is very different.
Electrostatic Potential Maps
The electrostatic potential can be mapped onto theelectron density by using color to represent the valueof the potential. The resulting model simultaneouslydisplays molecular size and shape and electrostaticpotential value. Colors toward “red” indicate negativevalues of the electrostatic potential, while colorstoward “blue” indicate positive values of the potential.
electron density
+
electrostatic potential
electrostaticpotential map
Are Resonance StructuresAlways Completely Truthful?
The two resonance structures for the zwitterion formof β-alanine show positive charge on nitrogen andnegative charge distributed equally onto the twooxygens.
H3N+CH2CH2CO
O–H3N+CH2CH2C
O–
O
This is reflected in the electrostatic potential mapwhich clearly shows that the ammonium group ispositive (blue) and that the carboxylate group isnegative (red).
Closer inspection reveals, however, that it is not thenitrogen which bears the brunt of the positive charge,but rather the attached hydrogens.
Why is More, Better?
Four resonance structures may be drawn for planarbenzyl cation, but only one may be drawn if thecarbocation center is twisted out of plane.
+
+
+
+
+
Why does this necessarily imply that benzyl cationwants to be planar?
Electrostatic potential maps show charge separationfor twisted benzyl cation, but almost no separationfor the planar cation.
Coulomb’s law (“separation of charge requiresenergy”) is responsible for the preference.
planar twisted
Molecular Orbital Models
Molecular orbitals are the solutions of the approximatequantum mechanical equations of electron motion.They are made up of sums and differences of atomicsolutions (atomic orbitals), just like molecules aremade up of combinations of atoms.
Molecular orbitals for very simple molecules are ofteninterpreted in terms of familiar chemical bonds, forexample, in acetylene.
This can be deceptive. While the two π molecularorbitals, like the two π bonds in acetylene, involveonly the two carbons, the σ molecular orbital is acombination of CC and CH σ bonds.
σ π π
Molecular Orbital Models
Sometimes unoccupied molecular orbitals provideimportant chemical insight. The lowest-unoccupiedmolecular orbital (the LUMO), in particular, demarksthe location of positive charge in a molecule. Forexample, the LUMO in planar benzyl cation is spreadout over four different carbons while the correspondingmolecular orbital in perpendicular benzyl cationresides primarily on only one carbon.
This is the same result provided by resonance theory.
H H+
+
+++
H H H H H H H H
planar benzyl perpendicular benzyl cation cation
Nucleophilic Additionto Enones
The LUMO of cyclohexenone is primarilyconcentrated on the carbonyl carbon and on the βcarbon. This is most clearly shown by mapping theLUMO onto an electron density model. Areas whichhave the greatest affinity for a nucleophilic are colored“blue”.
Both carbonyl chemistry and Michael additionchemistry are easily anticipated.
O
H
Nu
ONuHO
Nu Nu
Michael addition carbonyl
Why Bother . . .
with a computer when conventional models can easilybe constructed with a pencil?
The computer is the pencil of this generation. It’s useis no less familiar than that of the pencil, and molecularmodels . . . electron densities, electrostatic potentials,molecular orbitals . . . follow from an essentiallycorrect picture of molecular structure. They are bothmore general and more quantitative than thequalitative arguments in widespread use, and can beused to explore new chemistry.
Models that Move
Models need not be limited to static pictures. Ananimation is the best way to show atomic motions invibrating molecules. While other methods might beused for simple molecules such as water,
H HO
H HO
H HO
there really is no alternative for complex systems.
Models that Move
Animations also allow the motions of atoms during achemical reaction to be shown. For example,animation of the reaction coordinate for the pyrolysisof ethyl formate shows the simultaneous transfer ofthe hydrogen atom to the carbonyl oxygen along withcarbon-oxygen bond cleavage.
OC C
HOC
H
HH HH
ethyl formate
∆formic acid
ethene
O
C C
OCH
H
H HH H
OC C
HOC
H
HH H
H
Electron density models and electrostatic potentialmaps (in addition to structure displays) may also beanimated, showing electron motion.
ConceptualBackground
Potential Energy Surfaces
A potential energy surface is a plot of energy vs.reaction coordinate. It connects reactants to productsvia a transition state.
energy
reaction coordinate
equilibrium structures
transition state structure
Energy minima correspond to equilibrium structures .
The energy maximum corresponds to a transitionstate structure.
transition state
reactants
products
Potential Energy Surfaces
energy
reaction coordinate
"thermodynamics"
"kinetics"
The relative energies of equilibrium structures givethe relative stabilities of the reactants and products(thermodynamics).
The energy of the transition state relative to reactantsgives information about the rate of reaction (kinetics).
transition state
reactants
products
Potential Energy Surfaces
A reaction pathway may comprise several steps andinvolve several different transition states and reactiveintermediates. The rate limiting step in the overallpathway is that which passes over the highest-energytransition state.
energy
reaction coordinate
rate limiting step
The pathway with the lowest energy rate limiting stepis the reaction mechanism.
transition state
reactants
products
transition state
intermediate
Potential Energy Surfaces
Molecular modeling is primarily a tool for calculatingthe energy of a given molecular structure. Thus, thefirst step in designing a molecular modelinginvestigation is to define the problem as one involvinga structure-energy relationship.
There are two conceptually different ways of thinkingabout energy.
Molecular MechanicsA “Chemist’s” Model
Molecular mechanics describes the energy of amolecule in terms of a simple function which accountsfor distortion from “ideal” bond distances and angles,as well as and for nonbonded van der Waals andCoulombic interactions.
Coulombicinteraction
δ-
δ+
angledistortion
dihedraldistortion
van der Waals interaction
distancedistortion
Quantum MechanicsA “Physicist’s” Model
Quantum mechanics describes the energy of amolecule in terms of interactions among nuclei andelectrons. This is given by the Schrödinger equation,which may be solved exactly for the hydrogen atom.
8π2m-h2
2 + V(x,y,z) ψ(x,y,z) = E ψ(x,y,z)
∆
total energypotential energy
wavefunction describing the system
kinetic energy
The wavefunctions of the hydrogen atom are thefamilar s, p, d … atomic orbitals.
s p d
The square of the wavefunction gives the probabilityof 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 downfor many-electron atoms and molecules, it isimpossible to solve. Approximations are needed.
Schrödinger Equation HΨ = EΨ
Practical Molecular Orbital Methods
assume that nucleidon’t move
separate electron motions
get electron motion inmolecules by combiningelectron motion in atoms
“Born-OppenheimerApproximation”
“Hartree-FockApproximation”
“LCAO Approximation”
Molecular Modelingin Lecture
Molecular Modeling in Lecture
Molecular models can be introduced into almost anychemistry lecture. They not only liven the discussionwith “pretty pictures”, but more importantly encouragestudents to see and think for themselves. They freeteachers from the “limits of the chalkboard” and allowexamination and discussion of “real” molecules.
Visualizing Chemical Bonds
Are the different kinds of chemical bonds to whichchemists refer (nonpolar covalent, polar covalent andionic) fundamentally different? Look at electrondensity models for hydrogen fluoride, hydrogen andlithium hydride.
H-H H-F H-Li
The size of the electron density surface indicates thesize of the electron cloud. As expected, the size of thecloud surrounding hydrogen is smallest in hydrogenfluoride and largest in lithium hydride. Note, however,that in all three molecules the electrons are shared,although not equally. The bonds in all three moleculesare best described as covalent, although they differ intheir polarity.
Visualizing Chemical Bonds
An even clearer picture comes from electrostaticpotential maps, where the color red demarks regionswith excess negative charge and the color bluedemarks regions with excess positive charge.
H-H H-F H-Li
Hydrogen fluoride and lithium hydride look verysimilar, except that the hydrogen in the former ispositively charged while the hydrogen in the latter isnegatively charged.
The SN2 Reaction
N C N C CH3 + ICH3 I– –
An animation of the familiar SN2 reaction clearlyshows the inversion at carbon, but there are otherimportant questions.
The SN2 Reaction
Why does cyanide attack from carbon and notnitrogen? Doesn’t this contradict the fact that nitrogenis more electronegative than carbon?
Molecular orbital models provide insight. Look at thehighest-occupied molecular orbital of cyanide. Thisis 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. Lookat the lowest-unoccupied molecular orbital of methyliodide. This is where the electrons will go.
It is antibonding between carbon and iodine meaningthat the CI bond will cleave during attack.
The SN2 Reaction
We tell students that bromide reacts faster with methylbromide than with tert-butyl bromide because ofincreased crowding in the transition state of thetert-butyl system. This is not true. Space-filling modelsof the two transition states show both to be uncrowded.
What is true is that the carbon-bromine distance inthe transition state in the tert-butyl system is largerthan that in the methyl system.
2.5Å 2.9Å
The SN2 Reaction
This leads to an increase in charge separation as clearlyshown by electrostatic potential maps for the twotransition states.
This and not steric crowding is the cause of thedecrease in reaction rate.
Flexible Molecules
Interconversion of anti and gauche forms of n-butaneis readily visualized as a smooth rotation about thecentral CC bond.
We tell (show) students that all bonds are “staggered”in these structures.
Diaxial and diequatorial forms of trans-1,2-dimethyl-cyclohexane are very closely related to anti andgauche 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 ringundergoes the same type of conformational changeas n-butane. That is, it undergoes smooth rotation. Thedifficulty for the lecturer is that this change is not easilyportrayed by manipulating physical models. Thisobstacle is readily overcome with molecular models.
Note in particular:
i) The motion is smooth, just as it is in n-butane. Itdoesn’t “jump” as suggested by manipulatingphysical models.
ii) The motion corresponds to bond rotation, just asit 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 thenthe other end seems to move. This correspondsclosely to the usual (and very confusing) energydiagram found in virtually all organic textbooks.
energy
reaction coordinate
transition state(eclipsed)
twist-boat(staggered)diaxial
(staggered)
diequatorial(staggered)
transition state(eclipsed)
There is an intermediate (twist boat) and it too isstaggered. The two transition states involveeclipsing interactions.
Intermolecular Interactions
Acetic acid is known to form a stable hydrogen-bonded dimer. What is it’s structure?
O
H O
H
C CH3O
CO
H3C
O OC
OOC
H
HCH3H3C
O
HO C
O
CH3
CO
H3C
Look at an electrostatic potential map for acetic acid.
Which atom is positively charged and most likely toact as a hydrogen-bond donor?
Which atom is most negatively charged and mostlikely to act as a hydrogen-bond acceptor?
Intermolecular Interactions
Apply this same tool to a related question where youdon’t know the answer (or where you “know” thewrong 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 theperiphery (σ system) is electron poor. Stacking therings results in unfavorable Coulombic interactions,while a perpendicular arrangement of benzene ringsresults in favorable Coulombic interactions betweenπ and σ systems.
Intermolecular Interactions
The X-ray structure of crystalline benzene shows aperpendicular arragement!
Molecular Modelingfor Students
Molecular Modeling in theCurriculum
“Doing chemistry” with molecular modeling is a muli-step progress...not so different from doingexperimental chemistry.
Define Problem
Build Models
Do Calculations
Analyze Results
Given a “full” curriculum, the question that needs tobe answered is how much of this process to turn overto students.
One approach is to leave only the analysis of themodeling results (and learning the chemistry thatfollows from these results) to the student. Theadvantage of this approach is that it requires the fewestresources (hardware and software support, studenttraining), while guaranteeing high quality models andmaximum student-model interaction.
The Molecular ModelingWorkbook for
ORGANIC CHEMISTRY
A collection of over 200 problems arranged bychapters that parallel the contents of your organicchemistry textbook.
1 Lewis Structures and Resonance Theory2 Acids and Bases3 Reaction Pathways and Mechanisms4 Stereochemistry5 Alkanes and Cycloalkanes6 Nucleophilic Substitution and Elimination7 Alkenes and Alkynes8 Alcohols and Ethers9 Ketones and Aldehydes. Nucleophilic Addition10 Carboxylic Acid Derivatives. Nucleophilic Substitution11 Enolates and Nucleophiles12 Conjugated Polyenes and Aromaticity13 Electrophilic and Nucleophilic Aromatic Substitution14 Nitrogen-Containing Compunds15 Heterocycles16 Biological Chemistry17 Free Radicals and Carbenes18 Polymers19 Spectroscopy20 Mass Spectrometry21 Pericyclic Reactions
The Molecular ModelingWorkbook for
ORGANIC CHEMISTRY
Problems in each chapter address essential topics.
Chapter 11 Enolates and Nucleophiles
1 Keto/Enol Tautomerism2 H/D Exchange Reactions3 What Makes a Good Enolate?4 Enolate Acidity, Stability and Geometry5 Kinetic Enolates6 Real Enolates7 Enolates, Enols and Enamines8 Enolates are Ambident Nucleophiles9 Silylation and Enolates10 Stereochemistry of Enolate Alkylation11 Enolate Dianions12 Aldol Condensation13 Dieckmann Condensation
The Molecular ModelingWorkbook for
ORGANIC CHEMISTRY
Each problem uses one or more models, and studentsare required to look at and query these models to solvethe problem. The models are contained on a CD-ROMthat comes with the workbook, and can be viewed ona Mac or PC.
All models provide many types of informationobtained from molecular orbital calculations,including structure, energy and atomic charges. Manymodels also provide molecular orbitals, electrondensity surfaces and electrostatic potential mapsamong other graphical displays.
Models include many types of molecular species,including conformers, reactive intermediates,transition states and weak complexes. A number ofmodels involve sequences that can be animated.
Molecular ModelingSupplements to
Wade and BruiceOrganic Chemistry Texts
Collections of problems drawn from “The MolecularModeling Workbook for Organic Chemistry” andkeyed to the Wade and Bruice Organic Chemistrytexts, respectively.
McMurry and Carey OrganicChemistry Texts
• Extensive use of molecular models in text andaccess to models from SPARTANView
* From J. McMurry, Organic Chemistry, fifth edition, Brooks/Cole,PacificGrove, CA, 2000.
*
McMurry and Carey OrganicChemistry Texts
• End-of-chapter molecular modeling problemsrequiring use of SPARTANView or SPARTANBuild
* From J. McMurry, Organic Chemistry, fifth edition, Brooks/Cole,PacificGrove, CA, 2000.
*
McMurry and Carey OrganicChemistry Texts
• Essays describing molecular models and tutorialsillustrating their use
*
* From F.A. Carey, Organic Chemistry, fourth edition, McGraw-Hill,Columbus, OH, 2000.
. . . Bringing MolecularModeling to Students
• Tutorial for SPARTANBuild . . . an electronic modelkit
*
* From F.A. Carey, Organic Chemistry, fourth edition, McGraw-Hill,Columbus, OH, 2000.
Molecular Modelingin the Laboratory
A Laboratory Approach toMolecular Modeling
Student problems based on precalculated molecularmodels or lecture demonstrations using molecularmodels provide an incomplete picture. A “laboratory”approach in which students build their own models,do whatever calculations may be required and thenanalyze their findings (just like in an experimentalorganic laboratory) offers both students and teachersmuch greater flexibility. Because it puts studentsdirectly in contact with actual molecular modelingsoftware, it teaches them that calculations, likeexperiments, are not instantaneous, and that good“experimental design” is important.
A Laboratory Book ofComputational Organic
Chemistry1
This comprises a collection of 80+ “organicexperiments”, much like the experiments found in aconventional organic laboratory book. They cover avariety of topics and range of difficulty. The commonfeature is that they are “hands-on” and require studentsto use PC SPARTAN Pro or MacSPARTAN Pro. . . justlike “real” experiments require hands-on use ofglassware.
1. W.J. Hehre, A.J. Shusterman and W.W. Huang, A LaboratoryBook of Computational Organic Chemistry, Wavefunction,Irvine, CA, 1996, 1998.
Is Thiophene Aromatic?
Objective:
To quantify the “aromaticity” of thiophene.
Background:
Hydrogenation of benzene to 1,3-cyclohexadiene isendothermic, whereas the corresponding reactionstaking 1,3-cyclohexadiene to cyclohexene and thento 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 bondfor two C-H bonds, but in so doing destroys thearomaticity of benzene, whereas addition to eithercyclohexadiene or cyclohexene “trades” the samebonds but does not result in any loss of aromaticity.Therefore, the difference in the heats of hydrogenation(≈33 kcal/mol) corresponds to the aromaticstabilization of benzene.
elementary advanced
Is Thiophene Aromatic?
Procedure:
Calculate the energetics of hydrogen addition tothiophene and to the intermediate dihydrothiophene.
S S+ H2
S+ H2
The difference provides a measure of the aromaticityof 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
Objective:
To understand the difference between “thermodynamic”and “kinetic” reaction products.
Background:
Cyclization of hex-5-enyl radical can either yieldcyclopentylmethyl radical or cyclohexyl radical.
or
While the latter might be expected (it should be lessstrained, and 2° radicals are generally more stable than1° radicals), the opposite is normally observed, e.g.,
+Br +AIBN∆
17% 81% 2%
Bu3SnH
elementary advanced
Thermodynamic vs.Kinetic Control
Procedure (part A):
Calculate the energies of both cyclopentylmethyl andcyclohexyl radicals.
Question (part A):
What is the thermodynamic product of ring closure?What would be the ratio of major to minor productsat room temperature assuming that the reaction isunder thermodynamic control? (Use the Boltzmannequation.)
Procedure (part B):
Locate transition states for cyclization reactionsleading to cyclopentylmethyl and cyclohexyl radicals,and obtain their energies.
Questions (part B):
What is the kinetic product of ring closure? Whatwould be the ratio or major to minor products at roomtemperature assuming that the reaction is under kineticcontrol? (Use the Eyring equation.) Is the cyclizationreaction under thermodynamic or kinetic control or isit not possible to tell? Elaborate.
Molecular Recognition.Hydrogen-Bonded Base Pairs
Objective:
To model hydrogen-bonding between DNA base pairsin terms of charge-charge interactions. To identifynucleotide mimics.
Background:
The genetic code is “read” through the selectiveformation of hydrogen-bonded complexes, or Watson-Crick 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 thishydrogen bond-based code lies in the fact that virtuallyall aspects of cell function are regulated by properbase pair formation, and many diseases can be tracedto “reading” errors, i.e., the formation of incorrect basepairs.
elementary advanced
Molecular Recognition.Hydrogen-Bonded Base Pairs
Procedure (part A):
Calculate electrostatic potential maps for:
HN NCH3
O
O
CH3
N
N
NH2
N
N
CH3
N NCH3
O
H2N
HN
N
O
N
N
CH3
H2N
1-methylthymine(MeT)
9-methyladenine(MeA)
1-methylcytosine(MeC)
9-methylguanine(MeG)
Identify electron-rich and electron-poor sites thatwould be suitable for hydrogen bonding. Draw all basepairs that involve two or three hydrogen bonds.Choose one naturally occuring base pair and one thatdoes not occur naturally (maintain the number ofhydrogen bonds). Obtain geometries and energies forboth, and calculate the total hydrogen bond energy ineach.
Questions (part A):
What is the magnitude of the hydrogen-bond energyfor in the naturally occuring system? Is it as strong asa normal chemical bond? What is it in the systemwhich 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 hydrogenbonding properties of DNA nucleotides.
HN
O
H2N N
6-amino-2-pyridone(AP)
N-naphtharidinyl acetamide(NA)
N NH
O
Identify electron-rich and electron-poor sites for each,and examine the possible hydrogen bonded pairsinvolving AP or NA and one of the natural bases. Pickyour best candidate, obtain a geometry and energyfor the hydrogen-bonded complex and calculate thehydrogen-bonded energy.
Question (part B):
Is the magnitude of the hydrogen-bonding interactionin your mimic as large as in a natural base pair?
Proper Role ofMolecular Modeling
Focus on Chemistry
Modeling is a tool for doing chemistry. Molecularmodeling is best treated in the same way as NMR - asa tool, not a goal. A good model has the same value asa good NMR spectrum. Molecular modeling allowsyou to “do” and teach chemistry better by providingbetter tools for investigating, interpreting, explaining,and discovering new phenomena.
Don’t be Afraid
Modeling is accessible. Anyone can build a usefulmodel.
Modeling is “hands on”. Molecular modeling, likeexperimental chemistry is a “laboratory” science, andmust be learned by “doing” and not just reading.
Modeling does not need to be intimidating. Theunderpinnings of molecular modeling (quantummechanics) are certainly intimidating to manychemists, but so too are the underpinnings of NMR.Using molecular modeling should be no moreintimidating than obtaining an NMR spectrum.
Modeling is not difficult to learn and do. Molecularmodeling is easy to do given currently availablesoftware (probably easier than taking an NMRspectrum). The difficulty lies in asking the rightquestions of the models and properly interpreting whatcomes out of them.
