π-π (π-stacking) Interactions: Origin and Modulation

Larry Wolf

SED Group Meeting

01-18
18-11
 Stacking Geometries: An Electrostatic Tutorial
π-Stacking

++
 Hunter and Sander Rules: Geometry

Sandwich

Parallel displaced

Edge-to-face

Hunter, C. A.; Sanders J. K. M. J. Am. Chem. Soc. 1990, 112, 5525

Influence of differing pi electron density

Hunter, C. A.; Sanders J. K. M. J. Am. Chem. Soc. 1990, 112, 5525

Hunter and Sander Rules applied to Proteins (ala-ala)
(ala

Hunter, C. A. et al. J. Mol. Biol. 1991, 218, 837

 Substituent effects parallel stacked

Kcal/mol

Rotation barriers were measured by line shape

analysis in H-NMR

Cozzi, F.; Siegel J. S.; et. al. J. Am. Chem. Soc. 1992, 114, 5729
Cozzi, F.; Siegel, J. S.; et. al. Phys. Chem. Chem. Phys. 2008, 10, 2686
Polar/π vs charge transfer

Free energy of activation determined from 2D NMR EXSY

pulse sequence

Charge transfer does not contribute

significantly to the interaction

Cozzi F.; Siegel, J. S.; et. al. J. Am. Chem. Soc. 1993, 115, 5330
Face-to-face or center-to-edge?

- Rotation barrier determined by 2D EXSY NMR

- Mode of stacking is not well characterized
- low sensitivity may be a result of decreased favorable
electrostatic orientation

MMFF
Cozzi, F.; Siegel, J. S.; et. al. Org. Biomol. Chem. 2003, 1, 157
Parallel Displaced and/or edge-to-face
face or T-shape
T

X=F

G = RTLn(2) – RTLn(syn/anti)
Interaction is strongest when both rings
contain e-withdrawing
e groups?
OMe better fit with σ(meta)
Gung, B. W.; Xue, X.; Reich, H. J. J. Org. Chem. 2005, 70, 3641
Other pi-stacking Modes?

“The alternative T-shape

T orientation is prohibited by the
triptycene skeleton.”

T-Shaped geometry?

Gung, B. W.; Xue, X.; Reich, H. J. J. Org. Chem. 2005, 70, 3641
Double Mutant Cycle: edge-face/T--shaped

NOEs
(ROESY)

Hunter, C. A. et al. Angew. Chem. Int. ed. 1996, 35, 1542

Double Mutant Cycle: edge-face/T--shaped

Combined (meta and para ) equation

Hunter, C. A.; et. al. Chem. Commun. 1998, 775

Hunter, C. A.; et. al. Chem. Eur. J. 2002, 8, 2848
Double Mutant cycle: face-face

Based on NOE and δ values

Hunter C. A.; et. al. J. Am. Chem. Soc. 2005, 127, 8594
Electrostatic or Dispersion?

Crystal structure:
X=NO2; CH3

NMR experiments in
CDCl3

-0.56 kcal/mol

-0.43 kcal/mol

Wilcox, C. G. et al. J. Am. Chem. Soc. 1998, 120, 11192

 Benzene Dimer (Sandwich, T-Shaped,
Shaped, and Parallel Displaced)

Sandwich

T-Shaped

Parallel displaced

Energy

Distance
Sherrill, D. C.; et. al. J. Phys. Chem. A. 2004, 108, 10200
Decomposition of energetic components: Perturbation Theory

EA-B = Eelec + Eind + Evdw van der Waals (Lennard-Jones)

Evdw = Edisp + Erep

Erep Edisp
total

Sherrill, D. C.; et.al. J. Am. Chem. Soc. 2002, 124, 10887

Sherrill, D. C.; et. al. J. Phys. Chem. A. 2004, 108, 10200
Total Interaction energy and Dispersion

Eint traces a dispersive-like

potential with increasing distance
Sherrill, D. C.; et. al. J. Phys. Chem. A. 2004, 108, 10200
 Sherrill D. C.; et. al. J. Am. Chem. Soc. 2004, 126, 7690
Sherrill D. C.; et. al. J. Phys. Chem. A. 2006, 110, 10656
Substituent effects

σp 0 -0.37 -0.17 0.06 0.66

σm 0 0.12 -0.07 0.34 0.56

T(2)

T
 Kim K. S. et al. J. Am. Chem. Soc. 2005, 127, 4530

Substituent Effects

Type I

NO2, CN, Cl, OH, NH2

Type I Type II
 Sherrill D. C.; et. al. Phys. Chem. Chem. Phys. 2008, 10, 2646

Substituent effects in parallel-displaced:

displaced: energy profiles

All groups have a lower global

minimum than benzene
Energy decomposition

Dispersion: lowest change for F due to low polarizability, followed by OH then CN

Induction: slightly favors CN
Exchange:: minima represent minimal e-density
e in center of ring, dominates in CN
Electrostatics:: Positive at large displacements due to overlap of electronegative
group with negative electrostatic potential
Sherrill D. C.; et. al. Phys. Chem. Chem. Phys. 2008, 10, 2646
Revisiting the “molecular torsion balance”

Experiments
performed in
C6D6 compared
to that of
Wilcox’s in
CDCl3

Desolvation and ESP:

Diederich, F.; et. al. Angew. Chem. Int. Ed. 2004, 43, 5056
Hunter, C. A. Angew. Chem. Int. Ed. 2004, 43, 5310
 Hunter C. A.; et. al. Chem. Commun. 2006, 3806
Diederich F. et al. Chem. Commun. 2008, 4031
Desolvation or Eelec/Erep Modulation?

Diederich:
Diederich
Wilcox:
Desolvation counters

Based on (α + αs) between CDCl3 and C6D6, a large

sensitivity difference is not antipicipated

Hunter C. A.; et. al. Chem. Commun. 2009, 3961

Sandwich interaction in [4+2] cycloaddition

Me

OMe
Br

Houk, K. N. et al.; Swager T. M. et al. J. Am. Chem. Soc. 2010, 132, 3304
 Politzer, P.; Murray, J. S. In Reviews in Computational Chemistry; Lipkowitz, K. B., Boyd, D. B.,
Politzer
Eds.; VCH Publishers: New York, 1991; Vol. 2
Substituent effects on ESP
Molecular Electrostatic Potential (Multipole Expansion)

ESP vs ρ

Are substituent effects on ESP manifested by

polarization of π-electron density?

Compare ESPA and ESPB

with Hodgkin index (HAB)

Wheeler, S. E.; Houk, K. N. J. Chem. Theory Comput. 2009, 5, 2301

Hodgkin, E. E.; Richards, G. W. Int. J. Quantum Chem. 1987, 32, 105
 Wheeler, S. E.; Houk, K. N. J. Chem. Theory Comput. 2009, 5, 2301

Examples
Application of Method: Cation/π & Anion/π
Anion/
Cation/π Anion/π

Wheeler, S. E.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 3126

Wheeler, S. E.; Houk, K. N. J. Phys. Chem. A 2010, 114, 8658
Sandwich: minus one pi-surface?

Is all the variation in structure

that accounts for the observed
Eint be derived from the just the
substituent?

Attributed to Dispersion
(~-0.5 kcal)

Wheeler, S. E.; Houk, K. N. J. Am. Chem. Soc. 2008, 10854

Substituent Additivity

3F

3 CN 6F
6 NH2

6 CN

Dispersion forces are likely contributing

Wheeler, S. E.; Houk, K. N. J. Am. Chem. Soc. 2008, 10854
Sherrill, D. C. et al. J. Am. Chem. Soc. 2009, 131, 4574
Edge-to-Face aryl-aryl interactions

Wheeler, S. E.; Houk, K. N. Molecular Physics 2009, 107, 749

Global vs local dipole moment

Global dipole moment is insignificant

relative to individual dipoles

Wheeler, S. E.; Houk, K. N. Molecular Physics 2009, 107, 749

Conclusions

• Electrostatic-only
only (rather than donor-acceptor)
donor considerations illustrate
much of the observed experimental results (stacking orientation and
substituent effects)

• Substituent effects generally follow that predicted by the polar/

polar/ model
in the absence of significant dispersion contributions

• Gas phase calculations: dispersion forces are considered to be the

principle contributor to the overall interaction

• Relative role of desolvation and dispersion forces in solution (eg.

( CHCl3
and C6D6) is inconclusive

• Origin of electrostatic interaction may primarily result from through-

through
space interactions with the substituents for the majority of stacking
configurations