1) The document discusses computational studies of catalytic and oxidative reactions using quantum chemical methods like DFT. 2) It examines mechanisms of reactions like catalytic asymmetric reactions and oxidative cleavage of carbon-carbon double bonds. 3) Key findings include that B3LYP is sufficient for studying catalytic reactions while functionals like M06-2X provide more accurate energies, and weak non-covalent interactions play important roles in stereocontrol.

1. Richmond Lee
Quantum
Chemical
Studies into
Mechanism &
Reactivity of
Catalytic and
Oxidative
Reactions

2. Approach
2
Plausible?
1] Experimental observations
3] Choice/level of theory*
2] Propose mechanism
HΨ = EΨ
YES Rationalization for
Chemical Reactivity!
4] Modeling
NO
* Critical
Richmond Lee

3. Choice and level of theory
3
Plausible?
1] Experimental observations
3] Choice/level of theory*
2] Propose mechanism
HΨ = EΨ
YES Rationalization for
Chemical Reactivity!
4] Modeling
NO
* Critical
• DFT: fast optimization and
good geometries
• Composite methods or non-
canonical CCSD(T): highly
accurate scaled coupled
cluster calculations
• Speed and accuracy!
Richmond Lee

4. 4
Plausible?
1] Experimental observations
3] Choice/level of theory*
2] Propose mechanism
HΨ = EΨ
YES Rationalization for
Chemical Reactivity!
4] Modeling
NO
* Critical
Energy
FMO
Electron density
(topological)
Computational toolkit for chemical reactivity &
mechanism
Richmond Lee

5. 5
Materials,
eg polymers:
Degradation/
durability
Biomolecules:
Pathology/
disease
Catalyst:
Reactivity
Prediction/OutcomesIn silico modelingExperiments
Richmond Lee

6. - Part I -
Catalysis

7. 7
Cinchona Alkaloids Catalysts
Yield 60-70%
% enantioselectivity excess (ee) > 99
(DHQD)2AQN =
Chem. Eur. J. 2011, 17, 8066
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1 2
3

8. 8
Origin of stereoselectivity
ProposedMechanism
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9. 9
Origin of stereoselectivity
Outcome: agreement to experimentProposed
DFT B3-LYP functional with mixed basis set: 6-31G(d,p) on core atoms
and 6-31G(d) on other atoms. Values in parenthesis are PCM (toluene)
single-point energies.
Richmond Lee
COOMe
Ph
N
cis-R
cis-S
Nu
N
Ph
MeOOC
trans-R
trans-S

10. 10
*Cat
N
O
R1
H H
*Cat
N
H
O
R1
N
O
O
R3
R2
+ 9
-alkylation
-alkylation
Mechanism
Angew. Chem. Int. Ed. 2013, 52, 6666 Yield > 88%; % ee > 90
Mechanistic Questions:
• Stereochemistry?
• Why is γ-alkylation
preferred over α-
alkylation?
Richmond Lee
Thiourea Catalysts

11. 11
Regio- and stereo-selectivity
∆∆G‡ = 3.2
∆∆G‡ = 8.6 ∆∆G‡ = 5.5
∆∆G‡ = 0.0
Kinetically
preferred -
Agrees to
Expt.!
B3-LYP /6-31G(d,p)
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12. 12
Explaining regio- and stereo-selectivities
Values in parenthesis are Mayer bond orders*
*Bond orders were analyzed with AOmix
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13. 13
Catalysis: Chemo- and stereo-divergence
Mechanistic Questions:
• Origin of stereo- and chemo-selectivity?
• What causes the switch?
Angew. Chem. Int. Ed. 2016,
55, 1299
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14. 14Richmond Lee

15. 15
M06-2X(D3)/def2TZVP+SMD//B3LYP/6-31G(d,p)+SMD
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16. 16
Michael addition
Formal Mannich
Protonation
[4+2] product: first resting state
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17. 17
[4+2] product
retro-cyclization
Reorientation of substrates
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18. • B3-LYP, an economical DFT method is sufficient to
study catalytic asymmetric reactions: geometry
optimizations and even give accurate energies
• Improvement to energies could be done with a single-
point meta-hybrid M06-2X functional to correct for
deficiencies like dispersion effects
• Weak non-covalent interactions, eg non-classical H-
bonding Cα-H· · ·X (X= O,N) interactions play important
role in stereo-discrimination
18
Key findings - Part I
Richmond Lee

19. - Part II -
Oxidative Cleavage of Cholesterol by
Dual O2 activation and Sulfide
Reduction to Secosterol Aldehyde

20. 20
Oxidative C=C bond cleavage
Lin, Chen & Jiao, Org. Lett. 2012, 14, 4158
R2
R1
R4
R3
O3/ Zn or Me2S
Cat. Mn(III); Os(VIII); Ru(III)
Stiochiometric oxone/NaIO4
Organic oxidant: PhIO/ HBF4
enzymes: oxygenase; peroxidases
Review: Adv. Synth. Catal. 2013, 355, 3321
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21. Reactivity of triplet O2 with acene
21
Reddy & Bendikov Chem. Commun. 2006, 1179
UB3LYP/6-31G(d) level of theory
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22. 22
Metabolites have
pathological links to…
Heart disease
Alzheimer’s Parkinson
Inflammation
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23. Cholesterol metabolites causing Aβ aggregation
Kelly and coworkers, Proc. Natl. Acad. Sci. 2004, 4752
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24. AFM image of amyloid assemblies
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25. 25
HH
HO
H
3
Cholesterol
[O]
HH
HO
H
3
O
O
H
Aldol
HH
HO
H
OH
O
H
3
Susceptible to attack
to form plaque conjugate
HH
HO
H
3
O3
O
OO
HH
HO
H
3
O
OO
H
HO
H
3
O
O
O
Base/acid
Oxidation of cholesterol by oxidant
with chemical signature of ozone
Wentworth, Lerner and coworkers:
Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 3031
Science 2003, 302, 1053
NaO3S
N
H
O
SO3Na
O3
NaO3S
N
H
O
O2
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26. 26
J. Am. Chem. Soc. 2008, 130, 12224
Oxidation cleavage of C=C bond with singlet O2
Richmond Lee

27. DFT method
• Unrestricted broken-symmetry diradicaloid calculation
• Yamaguchi’s spin-projection energy to remove triplet
contamination
27
HSBS
SP
EEEBS )1(  
22
22
SS
SS
BSHS
LS
exact
HS



Functional/
6-31+G(d,p)
EBS EHS ESP
BS
HS<S2> BS<S2> ∆ES-T
B3LYP -150.3110038 -150.327576 -150.294430 2.0000 1.0000 20.8
M06-2X -150.2639480 -150.279856 -150.219285 1.9969 0.9969 28.0
M11 -150.2495452 -150.266872 -150.232213 2.0000 1.0000 21.7
M11-L -150.2238629 -150.244360 -150.203372 1.9997 0.9997 25.7
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28. 28
Broken symmetry UM11/6-
31+G(d,p) level of theory for
step-wise TS while
concerted TS are closed
shell optimized at RM11/6-
31+G(d,p).
Most preferred
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29. How about triplet ground state O2?
• Re-examine the C=C cleavage process
computationally by following…
– Only with ground state 3O2 molecule(s) to cleave
C=C bond of cholesterol
– Oxygen incorporation comes solely from O2
– Metal-independent process
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30. Retrosynthetic analysis
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31. 31
Triplet O2 addition to C=C bond
Energetically preferred
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32. 32Richmond Lee

33. 33
Peroxo reduction & C-C bond cleavage
J. Am. Chem. Soc. 1993, 115, 11376-11383; Antioxid. Redox Signal. 2003, 5, 577-582;
Antioxid. Redox Signal. 2013, 19, 823-835
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34. Theozyme modeling – mimicking enzyme
• ‘Theozyme’ or theoretical enzyme model by
Houk, Chen and Tantillo [Curr. Opin. Chem. Biol. 1998, 2,
743-750]
• Considers strategic placement of functional
groups that aim to stabilize the TS
• Goto & Klinman found methionine to be
important in O2 binding affinity in amine oxidase
[Biochemistry 2002, 41, 13637-13643]
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35. Richmond Lee 35

36. 36Richmond Lee

37. 37
Reactivity studies
Oxygen is more
polarized by Me2S
making it more
electrophilic
Binding chol to 2x 3O2 and
Me2S is exothermic
Non-polarized
oxygen
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38. 38
Entry Molecule ∆Gsol
≠ (kcal mol-1) N° (eV)
1 chol 27.2 0.102
2 styrene 27.8 0.110
3 isoprene 26.7 0.104
4 acrylate 34.9 0.037
5 butenone 32.4 0.063
6 vinyl methyl ether 30.8 0.098
Cyclohexenes & derivatives
7 R1= H, R2= H, R3= H 29.2 0.095
8 R1= CH3, R2= H, R3= H 27.0 0.107
9 R1= H, R2= CH3, R3= H 29.6 0.094
10 R1= H, R2= H, R3= CH3 29.3 0.094
11 R1=CH3, R2= CH3, R3= H 27.1 0.106
12 R1=CH3, R2= H, R3= CH3 26.6 0.107
N° is the global nucleophilicity
index of the alkenes
Richmond Lee

39. 39
Key findings - Part II
• New oxidative cleavage mechanism of C=C mediated
by dual 3O2 and sulfide reduction
• 3O2 addition rate acceleration with theozyme
• Reaction possible without photo-sensitizer
• Enzyme catalysis vs autoxidation
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40. - Part III -
Ozone in Promoting Polymer
Degradation
OO
n

41. Ozone reacts rapidly with rubber
41
Chem. Rev. 1930
Rubber cracking by ozone:
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42. Mass spec studies
42
pMMA with unsat. chain ends exposed to UV and heat to mimic outdoor conditions
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43. Defects or irregularities inherent in pMMA
43
Bulk
Benzene solvent
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44. O2 inhibition towards polymer degradation
44
NO + O3  NO2 + O2
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45. 45
Senescence of leaves
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46. 46
Dechelation of metal
[O]
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47. Further implications in fruit ripening?
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48. What do experiments tell us?
• [O] oxidation on pMMA is crucial for polymer
degradation
• Happens to chlorophylls for irreversible chemical
change in breaking C=C bond
• Which [O] oxidant is strong enough to break
C=C bonds?
• That is also naturally occurring in atmosphere?
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49. 49
O3 - Oxidative cleavage of double bonds
Ozone as oxidant for breaking C=C bonds
R2
R4
R1
R3
O3 R2
R4
R1
R3
O O
O
R1 R3
O
O
R2
O
R4
+
Primary ozonide
1,2,3-trioxolane
Criegee
Intermediate
R1
R3
O O
R2
O
R4
Secondary ozonide
1,2,4-trioxolane
R2
R4
R1
R3
O3 Zn
H2O R1
O
R3
+
R2
O
R4
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50. Addition of ozone to ω-unsat. bond
50
Values are G3(MP2)-RAD composite method free energies with solvent corrections in kcal mol-1
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51. 51
∆G≠ = +55.6
∆G≠ = +11.5
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52. O-O bond rupture
52
∆E = 58.6
Singlet channel
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53. 53
Singlet channel
∆G = +25.1
O-O bond rupture
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54. 54
Singlet channel
∆EMECP = +41.9
Minimum energy crossing point (MECP)
O-O bond rupture
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55. 55
Singlet channel
4
1.464
C2
O3
C4
D(O1‐C2‐O3‐C4) = ‐18.58°
O5
D(O5‐C4‐O3‐C2) = ‐12.16°
5
3.246
D(O1‐C2‐O3‐C4) = ‐63.26°
D(O5‐C4‐O3‐C2) = ‐40.94°
MECP
2.023
D(O1‐C2‐O3‐C4) = ‐15.96°
D(O5‐C4‐O3‐C2) = ‐28.54°
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56. 56
∆G≠ = +27.2
∆G≠ = +31.9
∆G≠ = +36.0
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57. 57
∆G≠ = +18.9
∆G≠ = +15.2
∆G≠ = +12.3
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58. 58
∆G≠ = +33.7
∆G≠ = +31.0
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59. • Experimental studies of the thermal degradation kinetics of PMMA
reported the process as having activation energy of 52.6 kcal/mol in
air.
• By assuming Arrhenius pre-exponential factors of both processes to
be similar, the ratio of kozone[O3]/kair[O2] offers a straightforward
comparison of their relative magnitudes.
• Under ambient conditions the concentration of O3 is 100 ppbv and
O2 2.1×108 ppbv. Using our computed MECP barrier of 41.9
kcal/mol and the experimental barrier of 52.6 kcal/mol, the computed
ratio of rate coefficients is ~33 at 298 K, implying that ozone initiated
damage to polymers is more than competitive, despite its very low
concentration
59
Key findings & conclusion
Richmond Lee

60. Richmond Lee 60
Work-in-progress
H
O3+
H
O3
cage
H
O3
step-wise
H
O O
O tertiary H abstraction
primary H abstraction
O3
H
HH
O
H
H
H
O
O
concerted
concerted
TS1a
TS1b
TS1c
TS1d
int-1
∆HRCCSD(T)
b ∆HRM11
d
iBu + O3 0.0 (0.026) 0.0
int-1 -0.4 (0.018) -1.8
TS1a 16.0 (0.018) 17.7
TS1b 23.6 (0.020) 27.1
TS1c 21.8 (0.051) 22.4
TS1d 34.2 (0.028) 29.5

61. Richmond Lee 61
Energy
FMO
Electron density
(topological)
Cost (not to scale)
Accuracy
CCSD(T) –
errors within
1 kcal/mol
Meta-hybrid DFT:
M06-2X, etc
MP2
Hybrid DFT: B3-LYP, etc
Semi-empirical: PM3, etc
Fast, accurate, and
communicable insights!
+

62. Thank you for
your attention…
Questions?
62Richmond Lee