1. -20
-15
-10
-5
0
0.9
1.1
1.3
1.5
1.7
1.9
2.1
2.3
2.5
-3 -2 -1 0 1 2 3
ΔEnergy(kcal/mol)
Distance(Å)
Reaction Coordinate (amu1/2•bohr)
Concerted Metalation Deprotonation (CMD) in C-H Functionalization: Computational
Study of Transition States
Jose Lopez, Sharon Neufeldt, Ken Houk
Background
Objective/Problem
Computational Methods
Results
Results (continued)
Conclusions and Future Work
Contact Information
Daniel Morton
Emory University
Department of Chemistry
1515 Dickey Drive
Atlanta
GA, 30322
Daniel.morton@emory.edu
404-727-5177
This work was supported by
the NSF under the CCI Center
for Selective C–H
Functionalization, CHE-
1205646
Any opinions, findings or
recommendations expressed
in this material are those of the
author(s) and do not
necessarily reflect the views of
the NSF
Acknowledgements
Dr. Monya Ruffin, CCHF Director of Education,
Outreach, and Diversity
Dr. Huw Davies, Director of the CCHF
Center for Selective C-H Functionalization
(CCHF)
2015 UCLA Summer Programs Undergraduate
Research (SPUR)
UC Leadership Excellence through Advanced
Degrees Program (UC LEADS)
National Science Foundation (NSF)
Concerted Metalation Deprotonation Mechanism
– In concerted metalation deprotonation (CMD), a ligand acts as a
base that facilitates C-H activation
Ex.
Why C-H Functionalization?
Direct substitution of C-H bond with C-C, C-O, or C-N
bond (no FG)
• Reduced steps in synthesis
• Reduced waste and byproducts
• Simpler (and cheaper) starting material
Image from: http://www.nsf-cchf.com/about/chf.html
C-H Functionalization
• Focus is on what are called “unreactive” C-H bonds
(pKa≥35)
• C-H bond breakage followed by forming of C-X
(where X=C,N,O)
• Usually direct cleavage that forms a C-M (where M is
a metal)
• Because of abundance of C-H bonds in organic
molecules, successful C-H activation must be selective
Question: How variable is the CMD TS?
• Hybridization
• Directing group
• Metal
• Ligand
Motivation: Variations in the mechanistic nuances could give insight into controlling
selectivity
• Acidity
• Strength of C-M
• Electrostatics
Density Functional Theory (DFT)
• Investigates structures based on electron density
• Many functionals available (this work: ωB97x-D; basis set: LANL2DZ for
metals and 6-31G(d,p) for all other atoms)
Calculations:
• Optimization = locate “best” geometry for structure
• Intrinsic Reaction Coordinate (IRC) = shows lowest energy rxn pathway
Transition States
Pd(OAc)2 + substrate
[M(Cp)(OAc) ]+ + dimethyl benzylamine (M=Group 9 metal)
ref. 1
ref. 2 ref. 3
ref. 4
arene sp2 C-H alkene sp2 C-H alkane sp3 C-H
RuLn + dimethyl benzylamine/2-phenylpyridine
arene sp2 C-H
Bond Distances and Energy Along IRC
-20
-15
-10
-5
0
0.9
1.1
1.3
1.5
1.7
1.9
2.1
2.3
2.5
-3 -1 1 3
ΔEnergy(kcal/mol)
Distance(Å)
Reaction Coordinate (amu1/2•bohr)
-20
-15
-10
-5
0
0.9
1.1
1.3
1.5
1.7
1.9
2.1
2.3
2.5
-3 -1 1 3
ΔEnergy(kcal/mol)
Distance(Å)
Reaction Coordinate (amu1/2•bohr)
● C-H
● O-H
● M-C
● Energy
-0.2
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
1
1.2
1.4
1.6
1.8
2
2.2
2.4
2.6
-10 -5 0 5 10
∆Charge
BondDistance(Å)
Reaction Coordinate (amu1/2•bohr)
-0.2
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
1
1.2
1.4
1.6
1.8
2
2.2
2.4
2.6
-10 -5 0 5 10
∆Charge
BondDistance(Å)
Reaction Coordinate (amu1/2•bohr)
● C-H
● C
Charge
Carbon Charge Change
Conclusions
• Gradual C-M bond formation
• Partial negative charge on C in TS
● C-H
● O-H
● M-C
● Energy
Future Work
• Continue to analyze IRC data for differences/trends (ex. correlation between ΔC-
charge and C-H bond breakage distance)
• TS with different substrate on arene
• Inspect preceding and subsequent intermediates and compare energies, bond
lengths, angles, etc.
– Relate barriers to features of TS
ΔG‡=?
ΔG=?
1. Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754-13755.
2. Davies, D. L.; Donald, S. M. A.; Al-Duaij, O.; Macgregor, S. A.; Pölleth, M. J. Am. Chem. Soc. 2006, 128, 4210-4211.
3. Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai, M. J. Am. Chem. Soc. 2014, 136, 5424-5431.
4. Özdemir, I.; Demir, S.; Çetinkaya, B.; Gourlaouen, C.; Maseras, F.; Bruneau, C.; Dixneuf P. H. J. Am. Chem. Soc.,
2008, 130 (4), 1156–1157.
-0.2
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
1
1.2
1.4
1.6
1.8
2
2.2
2.4
2.6
-3 -1 1 3
∆Charge
BondDistance(Å)
Reaction Coordinate (amu1/2•bohr)
● C-H
● C Charge