Organic Pedagogical Electronic Network

Non-Covalent Pi-System InteractionsElizabeth Bess

University of Utah

Non-covalent interactions with Pi systemsOverview: 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 non-covalent 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.

Pi-Pi Interactions:Cation-Pi Interaction:

Wiki Page: http://en.wikipedia.org/wiki/Non-covalent_interactionsOther 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

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.

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.

N

NNH

N

NH2

Adenine

Guanine

NH

NNH

N

O

NH2

Cytosine

N

NH

NH2

O

Thymine

NH

NH

O

O

H3C

DNA Bases

Designates base stacking

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 G-quartets 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.

N

NHN

N

O

N

N

N

NHN

O

N

N

N NH

N

O

N

N

N

HN N

O

N

H

H

H

HH

H

H

H

H

H

H H M+

N

NHN

N

O

N

N

N

NHN

O

N

N

N NH

N

O

N

N

N

HN N

O

N

H

H

H

HH

H

H

H

H

H

H H M+

N

NHN

N

O

N

N

N

NHN

O

N

N

N NH

N

O

N

N

N

HN N

O

N

H

H

H

HH

H

H

H

H

H

H H M+

G-Quadruplex

N

NHN

N

O

N

NN

NHN

O

N

N

N NH

N

O

N

NN

HN N

O

N

H

H

H

HH

H

H

H

H

HH H M+

G-Quartet

Molecular tweezers

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.

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 enamine-based 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).

HNNHO

O O

O

O O

HO

OH

O

OH

HO

O

Molecular Tweezer(Host)

NH

N

O

O

O

O

O

OHO

OHO

OH OHOH

O2N

O2N NO2

O

Host-Guest Pi-Pi Interaction

O2N

O2N

NO2

O

2,4,7-trinitrofluorenone(Guest)

Host Guest Host-Guest

Problems1. 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 sugar-phosphate backbone was presumed to contribute stability to the alpha-helical 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.

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?

2. When KCl is added to the DNA sequence (GGGGCC)4, a G-quadruplex forms. Why does this occur?

Face-Centered Stacking

OBase

O

O

P

O

OBase

O

O

OP

O

OBase

O

O

ODNA

O

POO

O

O Base

Base

OP

OO

O

O

Base

GNA

N

NH2H2N

Br

Ethidium bromide

4. Face-centered stacking of arenes is not energetically favorable. Provide a reason for this.

Solutions

References: Meggers, E.; Zhang, L. Synthesis and Properties of the Simplified Nucleic Acid Glycol Nucleic Acid. Acc. Chem. Res. 2010, 43, 1092-1102.

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.