Organic Pedagogical Electronic
Network
Non-Covalent Pi-System Interactions
Elizabeth Bess
University of Utah
Non-covalent interactions with Pi systems
Overview: Non-covalent interactions are the underpinnings of chemical selectivity, molecular recognition, and
supramolecular molecules’ tertiary structure (e.g., enzymes and DNA). These through-space, rather than through-bond,
interactions arise from attractions between oppositely and fully or partially charged species. One such class of noncovalent interactions are the intermolecular interactions of pi systems with other pi systems or charged species.
Arene Charge Distribution: The ability of pi systems to induce non-covalent interactions
with other partially charged species is understood via examination of the charge
distribution within an arene. Negatively charged electrons in the p-orbitals that comprise
the molecular orbitals of the pi system are localized above and below the arene plane.
Consequently, the arene plane bears partial positive charge. This charge distribution gives
rise to interactions of arenes through electrostatic attraction.
Cation-Pi Interaction:
Pi-Pi Interactions:
Wiki Page: http://en.wikipedia.org/wiki/Non-covalent_interactions
Other References: Hunter C. A.; Sanders, J. K. M. The Nature of π–π Interactions. J. Am. Chem. Soc., 1990, 112, 5525; Martinez, C. R.; Iverson, B. L. Rethinking the
Term "Pi-Stacking". Chem. Sci. 2012, 3, 2191-2201.
Pi-Pi/Cation interactions yield structural stability
DNA Helix: Pi stacking interactions are a key, potentially
dominant, stabilizing feature of DNA’s helical structure. As
the aromatic nucleobases orient to engage in favorable pi-pi
interactions, this influences a second stabilization event:
interstrand hydrogen bonding between base pairs.
DNA Bases
G-quadruplex: Four guanine bases arranged in a square
planar manner can engage in the non-covalent interaction
of hydrogen bonding to form a G-quartet. Stacking of Gquartets forms a G-quadruplex. Stability of this complex
increases with the number of stacked G-quartets due to the
stabilization afforded by pi-pi interactions. In the core of
these guanine complexes, which are lined with partially
negatively charged oxyegns, cations may coordinate to
afford additional stabilization.
In vitro formation of G-quadruplexes has been observed in
telomeres (a guanine-enriched portion of DNA that caps
chromatids). The formation of telomeric G-quadruplexes
has been implicated in reduced incidence of cancer.
Correspondingly, means of stabilizing these complexes
have been investigated.
Adenine
Cytosine
Guanine
Thymine
Designates base stacking
G-Quartet
G-Quadruplex
References: Matta, C. F.; Castillo, N.; Boyd, R. Extended Weak Bonding Interactions in DNA. J. Phys. Chem. 2006, 110, 563-578; Kool, E. T. Hydrogen
Bonding, Base Stacking, and Steric Effects in DNA Replication. Annu. Rev. Biophys. Biomol. Struct. 2001, 30, 1–22; Sponer, J.; Riley, K. E.; Hobza, P.
Nature and Magnitude of Aromatic Stacking of Nucleic Acid Bases. PCCP 2008, 10, 2595-2610; Davis, J. T. G-Quartets 40 Years Later. Angew. Chem. Int.
Ed. 2004, 43, 668-698; Huppert, J. L.; Balasubramanian, S. Prevalence of Quadruplexes in the Human Genome. Nucleic Acids Res. 2005, 33, 2908-2916.
Molecular tweezers
Application: Chemical probes have been developed to recognize specific molecular constructs amongst complex mixtures
of molecules. A “molecular tweezer” is one such probe that is designed to form favorable interactions with a guest molecule
via non-covalent interactions. Specificity for identifying particular motifs is engineered into the probe via thoughtful design of
interactions that the host may induce with a guest.
Engineering Pi-Pi Interaction Capabilities into Molecular Tweezers: The molecular tweezer, shown below, was
constructed to engage in pi-pi stacking interactions with a guest molecule. The guest is stabilized between the enaminebased arms of the molecular tweezer via pi-pi interactions. Evidence of the host-guest interaction is visually observed as a
color change from yellow-brown (either host or guest (not both) in dichloromethane solvent) to red-orange (host and guest in
dichloromethane solvent).
Molecular Tweezer
(Host)
2,4,7-trinitrofluorenone
(Guest)
Host
Guest
Host-Guest Pi-Pi
Interaction
Host-Guest
References: Legouin, B.; Uriac, P.; Tomasi, S.; Toupet, L.; Bondon, A.; van de Weghe, P. Novel Chiral Molecular Tweezer from
(+)-Usnic Acid. Org. Lett. 2009, 11, 745-748.
Problems
1. An interest in accessing double-helix species that are analogous to DNA
with greater synthetic ease has led researchers to investigate simpler
backbone structures for these analogs. While the natural-occurring sugarphosphate backbone was presumed to contribute stability to the alphahelical structure of DNA, it has been shown that this sugar-phosphate
backbone can be replaced with a glycol backbone to form glycol nucleic acid
(GNA). Interestingly, with this simplified backbone, the resulting GNA
molecule maintains a helical structure. Propose an explanation for this
observation.
2. When KCl is added to the DNA sequence (GGGGCC)4, a G-quadruplex
forms. Why does this occur?
DNA
GNA
3. Ethidium bromide is used to visualize DNA. In an aqueous solution, ethidium bromide does not fluoresce. However,
when in the presence of DNA, ethidium bromide will fluoresce and can be visualized with UV light. Why does ethidium
bromide fluoresce in the presence of DNA?
Ethidium bromide
4. Face-centered stacking of arenes is not energetically favorable. Provide a reason for this.
Face-Centered Stacking
Solutions
1. This observation may me due to stabilization of the helical structure through pi-stacking and hydrogen bonding
interactions of the base pairs, which remains conformationally accessible with a glycol backbone.
2. This structure is stabilized by the KCl because the K+ is favorably interacting with the pi system, which
favors the g-quadruplex structure more so than the hairpin loop.
3. The ethidium bromide is intercalating into the DNA strand which is a more hydrophobic environment. This causes
it to shed the water molecules, allowing it to fluoresce.
4.
References: Meggers, E.; Zhang, L. Synthesis and Properties of the Simplified Nucleic Acid Glycol Nucleic Acid. Acc. Chem. Res.
2010, 43, 1092-1102.