Molecular Modeling in Chemical Education and ... - Wavefunction, Inc.

Molecular Modeling in
Chemical Education and Research
Summer Tour 2005
Professor Richard Johnson
Chemistry Department
University of New Hampshire
rpj@cisunix.unh.edu
Sean Ohlinger
Wavefunction, Inc.
18401 Von Karman, Suite 370
Irvine, CA 92612
sean@wavefun.com
www.wavefun.com

What are we going to do today?
• Introduce you to molecular modeling and some of
its many applications in teaching and research.
• Introduce the newest versions of Spartan as tools in teaching.
• Introduce Odyssey, a new program for dynamic models.
• Demonstrate the Cambridge Crystal Structure Database
(CCSD) and its interface with Spartan.
• Give you plenty of time to have fun.
• Exchange ideas

What we won’t do today!
1. Overwhelm you.
2. Teach you the intricacies of Spartan and Odyssey.
3. Present the details of computational chemistry.

The Essential Elements
• Fast computers are now readily available. Today’s Pentium or PowerMac laptop is
much faster than yesterday’s mainframe computer.
• Sophisticated computational models are based on quantum mechanics and classical
mechanics.
• Recent development of the graphical user interface permits rapid construction of
models and spectacular visualization of the results. This has made molecular
modeling accessible to anyone.

Some things we often forget.....
• chemistry is about molecules
• molecules are three dimensional
• we can’t solve the Schrödinger equation exactly for
molecules but the approximate solutions are excellent

Sir John Pople 1925-2004
"I could have done it in a much more
complicated way," said the red Queen,
immensely proud.
- Lewis Carroll
“The essence of John Pople . . . to take
what is, or what seems to be, intractable
and make it so, so simple. Thank you,
sincerely thank you, for sharing your
precious gift with me, and with the
scientific world. You will be sorely
missed.”
Warren Hehre, President/CEO,
Wavefunction, Inc.

Essentials of Modeling
Build Structures: Many programs are just visualizers. Spartan allows
the rapid construction of virtually any structure in three dimensions.
Odyssey allows you to build your own molecular dynamics simulations.
Perform Computations: Force-field and quantum mechanical models
offer sophisticated descriptions of molecules, both known and
unknown. We can’t solve the Schrödinger equation exactly for
molecules but the approximate solutions are excellent.
Visualize and Interpret Results: Results include structure, energies,
molecular orbitals, electron densities, vibrational modes, dynamics
simulations, etc.
Recycle: Each answer often will lead to more questions and new
calculations.

Applications of molecular
modeling and visualization
•Research in industry and academics.
•Design of new pharmaceuticals.
•College graduate level coursework.
•College undergraduate coursework.
•On the worldwide web!
•Even in high school classrooms.

What can I do with modeling and visualization
in my classroom and laboratory?
•Enhance teaching of selected concepts and content.
•Emphasize the molecular nature of chemistry.
•Move from two dimensions into three.
•Show real 3 dimensional dynamic models – not just movies.
•Prepare course material and WWW images.
•Computational experiments in place of selected wet labs.
•Motivate students to be excited about chemistry.
•Research, enrichment and special projects.
•Advanced courses.
•Better prepare students for graduate school and future
careers in chemistry.

What can I do with modeling and
visualization in my research?
•Build and visualize complex structures in three dimensions.
•Import/export structures from/to other sources or projects.
•Use computations to model structure, conformation,
energetics, thermodynamics and chemical reactivity.
•Predict spectral properties: IR, UV-VIS, NMR shifts
•Predict new chemical reactions.
•Build and maintain a library of structures.
•Prepare images for presentations, web pages, publications
and proposals.
•Enhance my own professional training and credentials.
•Enhance my understanding of the literature.

Current Wavefunction Software
SpartanModel
an electronic model kit
Spartan ST
Student Edition
Spartan ’04
’06 is on the way….

What is
?
A New Set of Programs + Associated
Chemistry Content
for Teaching Concepts in
Introductory Chemistry
Odyssey is set to an accurate molecular scale
with time and molecular size greatly expanded.

An Introduction to Spartan

Spartan Architecture
Density
Functional
Semi-Empirical
Molecular Orbital
Ab Initio
Molecular orbital
Graphical
User
Interface
Molecular
Mechanics
External
Graphical
Surfaces
Properties

Building and Visualizing Structures:
Chemical evolution from methane to DNA

Current Wavefunction Software
SpartanModel
Spartan ST Student Edition
Spartan Essential
Spartan ’04
’06 is on the way….

Now that we know how to build
molecules, it’s time for bit of theory……

Theoretical Models
Methods Based on Quantum Mechanics: These are approximate Solutions to
the Schrodinger equation
•Semi–empirical :(CNDO, MNDO, ZINDO, AM1, PM3 etc.): based on the
Hartree-Fock self-consistent field (HF-SCF) method, valence electrons only,
approximations greatly simplify calculations, parameterized to fit experimental
results; recent extension to many transition metals.
•Ab Initio: (Non–empirical; from “first principles”): also HF-SCF but includes all
electrons and uses minimal approximation, large collection of methods and levels
of theory; increase in complexity for both basis functions and electron correlation.
•Density Functional: Based on electron density; includes electron correlation.
Methods Based on Classical Mechanics
•Force Field Methods: (MM2, MMFF, Amber, Sybyl, UFF etc.): based on
Hooke's law, van der Waals interactions, electrostatics etc.; parameterized to fit
experimental data. Also used to create dynamic models in Odyssey.

Schrodinger Equation
Nuclei don't move
Electronic Schrodinger equation
Guess how electrons affect
each other from idealized problem
1. Electrons move independently
2. Molecular "solutions" written
in terms of atomic solutions
Hartree-Fock
Molecular orbital methods
parameterization
AB INITIO
HARTREE-FOCK
MODELS
Mix in excited states
to account for
electron correlation
1. Atomic orbitals don't
interact.
2. Parameterization
DENSITY
FUNCTIONAL
MODELS
CONFIGURATION
INTERACTION
AND MOLLER-
PLESSET MODELS
SEMIEMPIRICAL
MO MODELS

Basis Sets for Computational Models
Semiempirical Methods: use Slater-type
functions; one size fits all
Ab Initio methods: most commonly used are Gaussian
functions; combination of Gaussians gives Slater-type
orbitals.
Increasing Complexity
Minimal basis set STO-3G
Split-Valence or Double-Zeta 3-21G(*)
Polarized basis sets 6-31G*
Extended basis sets 6-311+G**
Hartree-Fock limit: infinite basis set
unreliable
energetics
for most
accurate
calculations
excellent
results

Correlation energy: Electrons correlate their motion better than Hartree-Fock
theory allows for. This is typically a small portion of the total energy. Inclusion
of electron correlation lowers the energy of the wavefunction.
Hartree Fock
Energy
Correlation
Energy
Exact
Energy
Example: Methane Basis Set 6-311G*
Energy RelativeEnergy
(hartrees) (kcal/mol)
----------------------------------------------------------------------
E Hartree Fock -40.202409 0.0 kcal/mol
EMP2 -40.349308 -92.1
EMP3 -40.365949 -102.6
EMP4SDQ -40.369786 -105.0
EMP4 -40.372940 -107.0
B3LYP -40.527982 -204.2
When do you really need electron correlation?
Important for the most accurate calculations.
Essential for excited states, transition states, structures with
unusual bonding schemes, high-spin molecules….

Which computational method do you need?
Increasing level of theory
Correlated methods
(DFT, MP etc.
Ab Initio Hartree Fock
(3-21G, 6-31G* etc)
Semiempirical
(AM1, MNDO, PM3)
Force-Field
(MMF, Syby)
excited states, UV spectra, transition
state energies, structures with unusual
bonding schemes, most accurate
predictions of structure and properties
more accurate prediction of structure
and properties, NMR spectra, relative
energies of isomers, qualitative description
of transition states and reactions
basic description of structure and bonding,
vibrational spectra,, starting geometries for
higher level calculations
conformational analysis, starting
geometries for other calculations,
basic questions of structure and shape

Modeling Carbohydrate Complexes at Multiple levels of Theory

Approximate relationship between molecular
size and computational demands
AB INITIO
METHODS
CPU and MEMORY DEMANDS
SEMI-EMPIRICAL
METHODS
FORCE-FIELD
METHODS
MOLECULAR SIZE

Visualization

Vibrational Frequency Analysis
Stationary points on a potential surface are characterized by
vibrational frequency analysis. Vibrational modes may be
calculated and animated.
Energy minima will have all positive vibrational modes.
Energy maxima (first order transition states) will have a
single negative or imaginary mode. This corresponds to
the reaction coordinate. Higher order transition states exist
but they are rare. (Linear water for example!)
Calculated vibrational frequencies usually are ca. 10% too
high relative to experiment.

What is the significance of this structure?

Back to work…….What can we calculate?
Sample calculations on a simple molecule.
• Optimized structure
• Vibrational modes
• Surfaces

Charge and Multiplicity
singlet doublet singlet
CH 3
+
CH 3 CH 3
-

Electrostatic Potential Maps
The electrostatic potential is the energy of
interaction of a point positive charge (an
electrophile) with the nuclei and electrons of a
molecule. As a three dimensional isosurface, this
easily shows lone pairs. Hydrazine is shown here.
The electrostatic potential can be mapped onto
the electron density surface by using color to
represent the value of the potential. The
resulting model displays molecular size and
shape (from the density map) and is colored to
represent relative positive and negative regions
of the surface. Colors toward red indicate
negative values of the ESP, while colors toward
blue represent positive potential values. Sodium
chloride is shown in this example.

Visualizing Biomolecules:
Carboxypeptidase from a PDB File

Getting the word out….
Images and structures are easily transferred to:
• Powerpoint presentations like this one
• Word-processing programs
• JPEG files www pages
• AVI animations
• PDB files www pages and other programs
• Browser plugins like Chime (MDLI) offer
structure visualization on and off the WWW.

This is cool, but
is there a version
for
Macintosh?

What is
?
A New Set of
Programs +
Associated Chemistry Content
for Teaching Concepts in
Introductory Chemistry
Run Odyssey

…in the Introductory/General
Chemistry/High School Curriculum:
• Thermochemistry
.
• Gases
• Liquids/Solids/Intermolecular Forces
• Solutions
• Kinetics
• Chemical Thermodynamics

SPARTAN
vs.
Molecules / Small Clusters
Energy Minimization
(T = 0)
Small Molecule Chemistry
(Organic / Inorganic /
Medicinal / Biological)
Quantum Mechanics
Engine
Also:
Bulk Matter
Dynamics at Given
Temperature
Introductory / General /
Physical Chemistry
Classical
Molecular Dynamics
SImulation Engine
Integrated (DHTML)
Chemistry Content

…is interactive:
• Stop-’N-Go Dynamics
• Sample Manipulation
• Property Queries
• Plotting
…all “on-the-fly”,
initiated and controlled
by the student

Molecular Dynamics
Simulation Engine:
Newton:
F = m • a
dE (x 1 ,y 1 ,z 1 ,…)
dx 1
= m 1 •
dv x1
dt
Run Odyssey

Customization:
…annotate pages
…change sample(s)
…change text
…even create your own page !
Models can be created in Spartan and brought directly into Odyssey
to create new molecular dynamics simulations.

MD Simulations: Input
1. Positions x 1 ,y 1 ,z 1 ,… but really output in
“equilibrium” situations
2. Velocities v x1
,v y1
,v z1
, … basically temperature !
3. Force field force field:
E (x 1 ,y 1 ,z 1 ,…)
MMFF with extensions,
~ sufficient for pedagogical purposes

MD Simulations: Output
• Equilibrium structure
• Hydrogen bonds
• Spontaneous changes
• Response to perturbations
• Energetics / Thermodynamics
• Particle trajectories
• Diffusive behavior
• Rotational motion
…for the
chosen
temperature

Searching the Cambridge
Structure Database (CSD)
Wavefunction is now responsible for distribution of the Cambridge
Structural Database (CSD) System (on Windows and Unix) to academic
institutions in the United States.
The CSD currently contains more than 280,000 published X-ray crystal
structures for organic and organometallic compounds. About 20,000 new
structures are added annually. New versions of the CSD are released every
six months. The CSD System includes the ConQuest search software used to
interrogate all CSD information fields (bibliographic, chemical and
crystallographic), and also includes IsoStar, a knowledge-base of
intermolecular interactions and Mercury, a visualization and analysis
program.
Structure searching can be done directly through
Spartan and structures are easily imported.

Searching the Cambridge Database

Searching the Spartan Database

Applications of Spartan
•Teaching basic concepts: atomic orbitals,
acidity, resonance, chemical bonding
•Using lists
•Conformational analysis
•Coordinate driving
•Transition state searching
•Visualizing reactions
•Examples from inorganic chemistry

Atomic Orbitals: The Bromide Ion HF/3-21G Results
Atomic configuration: 1s 2 2s 2 2p 6 3s 2 3p 6 3d 10 4s 2 4p 6
Atomic Orbital Energies
eigenvalues: -486.69845 1s
-64.66592 -57.85828 -57.85828 -57.85828 2s,2p
-9.52913 -7.10100 -7.10100 -7.10100 3s,3p
-2.83570 -2.83570 -2.83570 -2.83570 -2.8357 3d
-0.63114 -0.08504 -0.08504 -0.08504 4s,4p

4p
4s
3d
ENERGY
3p
3s
2p
2s
1s

Acidity: Oxoacids of Halogens
hypochlorous acid
chlorous acid
chloric acid
perchloric acid
(hypochlorite ion)
(chlorite ion)
(chlorate ion)
(perchlorate ion)
HClO ↔ H + + ClO -
HClO 2 ↔ H + + ClO 2
-
HClO 3 ↔ H + + ClO 3
-
HClO 4 ↔ H + + ClO 4
-
K a = 3.0x10 -8
K a = 1.0x10 -2
K a = 1.6x10 1
K a = 1x10 10
(weak)
(strong)

Ionic vs. Covalent Bonding: Salt
Calculate sodium chloride at the ab initio HF/3-21G(*)
level of theory.
Visualize electron density, electrostatic potential maps
And charges.

Plotting Data: Constraints, Lists and Spreadsheets

Animating the Inversion Barrier in Ammonia

3D Plots may also be useful

Using Lists and Spreadsheets: Conformations of Cyclohexane
Other examples: shapes, radicals, HX polarization, alkane series, forms of carbon
benzene MO’s, covalent vs. ionic bonding, ozonolysis energetics, polyene UV,
benzene isomers, benzonitrile nitration, hydroboration

NMR Spectral Calculation
Another example

Example: Conformations of Octane

Visualizing Chemical Reactions
Locate the transition state
Calculate the intrinsic reaction coordinate
Animate the transition state “imaginary” vibrational mode

Starting anwhere in
this region of space
will usually find the
minimum.
To find a transition state
you MUST start with a
guessed geometry in
this region of space

Stationary point: a molecular geometry where all forces on atoms are zero
(or minimized to tolerances set in programs.)
1) Energy minimum: easy to find but there are often many conformations.
Frequency analysis will give all positive vibrational frequencies.
2) First order saddle point or transition state: more difficult to find because
you must start with a guessed geometry that is close to the answer.
Frequency analysis will give one “imaginary” frequency which corresponds
to the reaction coordinate.
3) Higher order saddle point: a transition state in more than one direction.
Frequency analysis will give two or more imaginary frequencies. Simplest
example may be linear water.
TRANSITION
STATE
ENERGY
REACTANT
PRODUCT
REACTION COORDINATE

Modeling Transition States
Diels-Alder TS Migratory insertion in CH 3
Mn(CO) 5

Strategies for Finding Transition State Structures
If you can find one TS, you have them all.
Find the simplest TS for the reaction first; then build on the rest of your molecule
and partially optimize with the important structural components frozen.
To examine regio- and stereochemical issues, build as many copies as you need
in a spreadsheet and optimize them all in one job. This is an extraordinarily
powerful technique.

Strategies for Finding Transition State Structures
Use bond lengths or other constraints to pre-optimize a guess.
Bonds that are being broken or made usually are 20 – 50% longer in
transition state structures. Look at related structures for guidance. Data
often are highly transferable from related TS structures.
This is almost always MUCH easier to accomplish in Spartan.
NC
H
C
Cl
2.126
H
TS bond C--H bond length is
ca. 1.4 - 1.5 Angstroms
Diels-Alder TS usually has
C----C bond lengths of
1.9 - 2.3 Angstroms
H H
2.397
B3LYP/6-31G*
S N 2 has pentacoordinate
carbon and two long bonds

Strategies for Finding Transition State Structures
Use the transition state library in Spartan: draw arrows corresponding to
the mechanism. The library includes thousands of transition states.
Hints:
1) Draw arrows in a continuous direction
2) Use the INSERT key to place several molecules on screen
3) Some arrows are drawn bond to bond
4) To draw arrows to a space, hold down the
shift key and click on two atoms separating the new bond.
5) You can begin on either side of a reaction.

A Research Example: Synthesis of Panepophenanthrin (2003)
O
HO
Me
Me
O
OH
O
OH
O
H
H
HO
O
R
R
O
Eight possible
modes of
cycloaddition
X. Lei., R. P. Johnson and J. A. Porco Jr.
Angew. Chem. Internat. Edit. 2003,42, 3913.
R = C(OH)(CH 3 ) 2
O
Me
OH
Me
Me Me O
OH
H O
H
OH
OH
O
panepophenanthrin
O
HO
Me
O
Me
Me
H
H
OH
OH
OH
Me
O

Intrinsic Reaction Coordinate (IRC) Searches
An IRC calculation starts with the TS geometry and Hessian, then locates the
minima connected to this TS. This begins by following the “imaginary”
vibrational mode. IRC calculations are time consuming since each point must
be optimized on the surface.
IRC calculations are
the most reliable way to
prove that you have
found the correct TS.

Examples from Inorganic Chemistry
Berry pseudorotation in PCl 5
Zr benzyne complex
ethylene insertion
Migratory insertion in
CH 3
Mn(CO) 5

Visualizing a chemical reaction: Nucleophilic Substitution
NC
-
H
H
C
H
Br
NC
H
C
H
H
Br
NC
C
H H
H
Br
-
Visualization of the HOMO best shows the negative
charge location. This begins on the nucleophile and
migrates to the leaving group. The animation also
shows the inversion of stereochemistry. Drawing
electron density slices shows bonds forming and breaking.
Stereocenter inversion , SN2 examples

Visualizing an SN2 Reaction
HOMO
Electron Density Slice

Molecular Recognition.
Base Pairing
Nonactin-Potassium
Complex

Wrapping up: What can you do with molecular
modeling and visualization in your classroom and laboratory?
•Enhance teaching of selected concepts and content.
•Emphasize the molecular nature of chemistry.
•Move from two dimensions into three.
•Show real 3-D dynamic models – not just movies.
•Prepare course material and WWW images.
•Computational experiments in place of selected wet labs.
•Motivate students to be excited about chemistry.
•Research, enrichment and special projects.
•Advanced courses.
•Better prepare students for graduate school and future careers in
chemistry.
Now it’s up to you….