mount st. helens, wa, usa, may 18, 1980
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1© David Gallagher 2002Mount St. Helens, WA, USA, May 18, 1980
David Gallagher *
Modeling Chemical Reactivity Visualization of chemical reactivity Kinetic & thermodynamics
2© David Gallagher 2002
Visualization of Reactivity
Susceptibility to electrophilic attack? (phenol)
* K. Fukui et al, J. Chem. Phys., 11. 1433-1442 (1953)** Also, nucleophilic, radical, electrostatic potential, superdelocalizability, etc.
HOMO onelectron
iso-densitysurface
HOMO
Largest HOMO density on para & ortho positions
Partial charges
Largest negative charge on para & ortho positions
••+-
Fukui’s Frontier Density*
Electrophilic susceptibility**
Highest frontier density on para & ortho positions
3© David Gallagher 2002
Susceptibility to Attack
*Fukui’s frontier density on electron isodensity surface
Electrophilic(occupied obitals)
Nucleophilic(unoccupied orbitals)
Radical(all valence orbitals)
4© David Gallagher 2002
Polyester Weatherability*
• New methyl propane diol based Polyester introduced
• Competitor claims “Norrish type II” degradation mechanisms
mean rapid degradation of diols with beta hydrogens under UV
radiation, unlike competitor’s neopentyl based polyester
H
methyl propane diol neopentyl diol
5© David Gallagher 2002
• Experimental accelerated test results inconsistent with “Norrish”
• “Radical susceptibilty” surfaces similar for both polyesters
* Published in Journal of Coatings Technology Vol. 67, No. 847, August ‘95
by Carl J. Sullivan & Charles F. Cooper, ARCO Chemical Company
CAChe & Tests Disprove Claims*
methyl propane polyester neopentyl polyester
H
6© David Gallagher 2002
Conrotatory sterically hindered
Insights into Catalysis
A. R. Pinhas, B. K. Carpenter, J.C.S. Chem. Comm., 1980, 15.
tricyclo-octadiene bicyclo-octatriene
X
Why does iron tricarbonyl apparently catalyse this reaction?
Fe(CO)3
Disrotatory ?
7© David Gallagher 2002
Frontier MO Control of Stereochemistry
• Thermal reaction: most reactive electrons in HOMO
Conrotatory
Sterically hindered
CAChe MOPAC AM1-d
Disrotatory
Sterically allowed
Fe
• Iron carbonyl changes symmetry of frontier orbital (HOMO)
8© David Gallagher 2002
Improve Yield, Minimize Byproducts
83% syn
17% anti
methylnitrone
monofluoroallene
+ ?
• Thermodynamic control? Isomers have same Hf, - No!
• Kinetic control? syn-product T-state is lower energy, - Yes!
• Why is syn lower? Visualize energy terms of T-state*
*Purvis III, G. D., J. Computer Aided Molecular Design, 5 (1991) 55-80
-ON+
CF
N
O
F
N
O
F
9© David Gallagher 2002
Sterics of the Transition-state
• Sterics, Frontier orbitals & Electrostatics all influence transition state
• Sterics slightly favor anti-product: but inconsistent with experiment (17%)
anti-addition (17%) syn-addition (83%)
methylnitrone
MFA
sterichindrance?
10© David Gallagher 2002
Orbitals of the Transition-state
• Closest energy frontier orbitals are nitrone HOMO & MFA LUMO
• Frontier orbital overlap suggest both transition states equally allowed
anti-addition (17%) syn-addition (83%)
nitroneHOMO
MFALUMO
+
+
+
+
+
+
+
+
11© David Gallagher 2002
Electrostatic Control of Yield
• Anti-addition shows +/+ repulsion, syn seems energetically favored
• Product ratios are consistent with electrostatic control (strongest long-range)
• Thus, changing solvent (dielectric) or substituents could control product yield
anti-addition (17%) syn-addition (83%)
nitrone
MFA
red: +ve
blue: -ve
Electrostatic isopotential surfaces: proton repelled by 20 kcals on red surface.
+/+
12© David Gallagher 2002
Visualization of Reactivity
* K. Fukui et al, J. Chem. Phys., 11, 1433-1442 (1953)
Electrostatics (AM1)
partial charges (menu)
electrostatics on surface
electrostatic isopotential
Frontier orbitalsHOMO, LUMO, etc.
susceptibility*, (substrate only)
superdelocalizability*, (both reactants)
Stericsspace-filling
VdW (electron isodensity)
MM conformation search
13© David Gallagher 2002
Thermodynamics & Kinetics
1. Thermodynamics (heat of reaction) Eproducts – Ereactants
Heats of Formation are calculated by MOPAC PM3http://www.shodor.org/UNChem/advanced/kin/arrhenius.html
Reactant Er
Energy of reaction = Ep – Er
Product Ep
Activation energy Ea = Et – Er
T-state Et
2. Kinetics (activation energy) Etransition-state - Ereactants
k = A*exp(-Ea/R*T)
14© David Gallagher 2002
Substitution Position by Kinetics
Lowest energy* transition state = fastest reaction = main product
2) Ortho: 171 Kcals1) Para: 167 Kcals 3) Meta: 183 Kcals
Br
Br
Br
Transition states for electrophilic attack by Br+ on phenol
15© David Gallagher 2002
Urethane Polymerization Reaction
• Lower temperature would reduce costs and thermal decomposition
R-N=C=O + CH3OH = RNHCOOCH3
R
Catalyst
*Malwitz, N., Reaction Kinetic Modeling from PM3 Transition State Calculations, J. Phys. Chem., Vol 99, No. 15, 1995 p. 5291
R Catalyst Solvent Activation Emethyl 43.7 kcalphenyl 41.3 kcalmethyl N(CH3)3 32.0 kcalphenyl N(CH3)3 26.9 kcalphenyl N(CH3)3 CH3OH 16.7 kcal
• Model transition states, then calculate catalyst & solvent effects
• To save time & money, CAChe used to explore reaction conditions
Project successful, saving many months& cost of chemicals for pilot scale
16© David Gallagher 2002
Unexpected Insights
R
Catalyst
*Malwitz, N., Reaction Kinetic Modeling from PM3 Transition State Calculations, J. Phys. Chem., Vol 99, No. 15, 1995 p. 5291
• Literature states lone-pair of trimethylamine ‘attacks’ + of carbonyl ‘C’
• Modeling does NOT support this (lone pair of catalyst attaches to proton)
• New insight reveals alternative (or true?) mechanism
17© David Gallagher 2002
Polyurethane: “Summary”
“... capable of offering insight useful toward
• minimizing unwanted side reactions
• optimizing yields
• suggesting reaction conditions
• and determining polymer composition...”
*Malwitz, N., Reaction Kinetic Modeling from PM3 Transition State Calculations, J. Phys. Chem., Vol 99, No. 15, 1995 p. 5291
18© David Gallagher 2002
CPD Dimerization & Temperature
* G = H - T S
* * *
Exo
ther
mic
En
do
ther
mic
low temp
high temp
19© David Gallagher 2002
Hf RMS errors (kcal.mol-1) compared to experiment
*Comparison of the accuracy of semiempirical and some DFT methods for predicting heats of formation, James J. P. Stewart, J Mol Model (2004) 10:6-12
MOPAC & DFT Accuracy
Errors in Heats of Formation (kcal/mol)*No. in set RMS error Max. error
MNDO 1,238 29.69 178.8AM1 1,238 13.80 86.1PM3 1,238 7.82 38.1PM5 1,238 6.65 33.8DFT B88-LYP (DZ) 1,238 8.50 40.3DFT B88-PW91 (DZ) 1,238 8.51 39.8
20© David Gallagher 2002
Strategies for locating T-States
1. Sketch a ‘guess’
2. Modify similar TS
3. Map reaction
4. Search for saddle
21© David Gallagher 2002
Map the Reaction
Screen capture with “SNAP32”, AVI movie made with “GIF Movie Gear”
Diels Alder
MOPAC PM3 Optimized Grid
22© David Gallagher 2002
Reactant Product
2. Copy & name it “Product”
Search for Saddle (keto-enol)
1. Sketch “Reactant” with atom #s
T-state
4. Copy “Reactant”, name “T-state”
3. Edit to “Product” structure
5. Experiment: Search for Saddle
23© David Gallagher 2002
Verifying the T-State
1. Refine
2. Verify (IR spectrum)
24© David Gallagher 2002
Verify Transition State
3. Do calculated bond-orders seem reasonable?
“View | Pt. Chg. & Calc. Bond Order”
2. Do atom-distances seem reasonable?
“Adjust | Define geometry label”
1. Single negative
vibration?
“Verify T-state”
25© David Gallagher 2002
Intermediates?
? ?
Intrinsic Reaction Coordinate (IRC)
26© David Gallagher 2002
Reaction Path (IRC)
Intrinsic Reaction Coordinate (IRC)
Water-catalyzed keto-enol tautomerization, reaction path
27© David Gallagher 2002
Solvents & Radicals
28© David Gallagher 2002
Summary for locating T-States
1. Create an approximate T-state
2. Refine (consider solvents & radicals)
3. Verify (neg. vibration, bonds)
4. Check reaction path for intermediates
29© David Gallagher 2002
Safe Laboratory Practice
“The purpose of computing
is insight, not numbers”
Amdahl
“Calibrate before use!”
(experiment or ab initio)
Old Chemists never die… they simply fail to react
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