Fundamentals of

Biochemistry
CHEM 461
Week 1
Non-covalent Interactions

Bilkent University
Department of Chemistry

Instructor: Dr. Yunus Emre Türkmen

 Non-covalent Interactions:
The Classical View

Ø Dipole - dipole interactions

-Hydrogen Bonding
Ø Ion - dipole interactions
Ø Dipole - induced dipole interactions
Ø Ion – induced dipole interactions
Ø Induced dipole – induced dipole interactions
- London dispersion
Non-covalent Interactions:
The Classical View
 Non-covalent Interactions:
Expanding the Scope

R'
Hydrogen Bonding O H N R H O
Weak Hydrogen Bonds R'
H
F F CH-π, CH-O, OH-π, etc. R'
O H
Halogen Bonding F I N R
R'
F F

π-π Stacking

M+
Solid State Solution
Cation-π Interaction

X-
F F
Anion-π Interaction F F Function
F F
Hydrogen Bonding: IUPAC Definition

Pure Appl. Chem. 2011, 83, 1637-1641.

Hydrogen Bonding: List of Criteria

Pure Appl. Chem. 2011, 83, 1637-1641.

Hydrogen Bonding: Some Characteristics

Pure Appl. Chem. 2011, 83, 1637-1641.

Hydrogen Bonding between two Water Molecules
Desiraju, G.; Steiner, T. “The Weak Hydrogen Bond in Structural Chemistry
And Biology”, 2001, p. 12.
 Properties of Very Strong, Strong and Weak
Hydrogen Bonds

Desiraju, G.; Steiner, T. “The Weak Hydrogen Bond in Structural Chemistry

And Biology”, 2001, p. 13.
DNA Double Helix
Sugar Phosphate Backbone of DNA
Structures of the Four DNA Bases (Nucleobases)
Watson-Crick Base Pairs
 Examples of Triple
Hydrogen-Bond Arrays

Leigh and co-workers,

Nat. Chem. 2011, 3, 244-248.
Examples of Quadruple Hydrogen-Bond Arrays

Leigh and co-workers,

Nat. Chem. 2011, 3, 244-248.
 Hydrogen Bonding Catalysis: An Emerging Field
A Case Study

Catalysis of Hetero-Diels-Alder Reactions using

Hydrogen Bond Donors:

Rawal and co-workers, J. Am. Chem. Soc. 2002, 124, 9662-9663.

Enantioselective Diels-Alder Reactions Catalyzed by
Hydrogen Bond Donors

Rawal and co-workers, Nature

2003, 424, 146.

Rawal and co-workers, PNAS

2004, 101, 5846-5850.
Halogen Bonding: IUPAC Definition

D⋅⋅⋅X-Y :

Pure Appl. Chem. 2013, 85, 1711-1713.

Understanding Halogen Bonding:
the σ-hole

Clark et. al.

J. Mol. Model. 2007, 291.
 Spartan Calculations of Electrostatic
Potential Surfaces

C6H5I top and

side views

C6F5I top and

CCl4 side views

red: negative; blue: positive

Examples of Halogen Bond Donors and Acceptors

Diederich and co-workers,

Angew. Chem. Int. Ed. 2015,
DOI: 10.1002/anie.201408487
 General Properties of Halogen Bonding
Ø The strength of the halogen-bond donor increases in the order Cl<Br<I
Ø Halogen-bond ability increases for R-X as the electronegativity of R
increases
Ø Halogen bonding is highly directional; for D···X-Y, angle is close to
180o and also the bond develops along the lone pair e- axis
Ø The forces involved in halogen bonds are primarily electrostatic, but
polarization, charge transfer (n→σ* interaction) and dispersion
contributions may play an important role.
Ø N- Lewis bases (amine and pyridine derivatives) generally form
stronger halogen bonds than O and S compounds (ethers, alkols,
thioethers, etc)
Ø For D···X-Y type complexes, D-X distance is shorter than the sum of
the VdW radii of D and X, and X-Y bond lengthens slightly
Ø Halogen bond strengths can be sometimes comparable to those of
hydrogen bonds
 Applications of Halogen Bonding

Ø Crystal Engineering
Ø Liquid Crystals
Ø Control the structural and physical properties of
conducting and magnetic materials
Ø Separation of isomers
Ø Supramolecular control on the reactivity in solid state
Ø Optimize the binding of ligands in a receptor, molecular
folding and other biopharmacological properties
Ø Catalysis
Ø Anion Binding Receptors
 Halogen Bonding in MEK1 Kinase Inhibitors

J. Med. Chem. 2007, 50, 5090-5102.

 Halogen Bonding in Human Aldose Reductase-
Inhibitor Complex

ØIDD 594 binds to AR 1100 times better

than to aldehyde reductase which has
a Tyr in place of Thr
ØReplacement of Br with Cl increases the
Podjarny et. al.
IC50 value by a factor of 2.3
Proteins, 2004, 792.
Benzene Dimers: Edge-to-Face and π-π
Interactions
A Double Concave Hydrocarbon Buckycatcher
X-ray Structure of the 1:1 complex:

Ø π-π interactions
Ø Complexation occurs in solution as well
Ø Ka = 8600 ± 500 M-1 in toluene (NMR titration)

Sygula and co-workers, J. Am. Chem. Soc. 2007, 129, 3842-3843.

7-methylated GTP sandwiched between two tryptophan side chains:

J. Mol. Biol. 2002, 319, 615-635.

 Cation-π Interaction in the Gas Phase:
Early Studies

Kebarle and co-workers, J. Phys. Chem. 1981, 85, 1814-1820.

Meot-Ner and co-workers, J. Am. Chem. Soc. 1985, 107, 469-474.
Cation-π Interactions in the Gas Phase
Cation-π Interactions in Water
 Cation-π Interactions in Catalysis

Dougherty and co-workers, Angew. Chem. Int. Ed.

1990, 29, 915-918.
Transition State Stabilization

Dougherty and co-workers, Angew. Chem. Int. Ed.

1990, 29, 915-918.
Cation-π Interactions in Biological Systems
The Aromatic Box in Acetylcholine Binding Proteins
Three tyrosine and two tryptophan amino acids:

Dougherty, D. A. Acc. Chem. Res. 2013, 46, 885-893.

Cation-π Interactions in Glucoamylase
 Anion-π Interac.ons
X- X- X-
F F F H O
N N
F F F N O NH
N N
F F F H O

≈20-50 kj mol-1
First experimental evidence in 2004
Reviews on Anion-π Interac.ons:
Angew. Chem. Int. Ed. 2011, 50, 9564.
Johnson, D. W. et al. Inorg. Chem. Front. 2014, 1, 35.
Chem. Commun. 2006, 506.

R Ka (M-1)
R
N Me 60
H
Ph 30
NH HN
H 4-N3-Ph 40
N
R 4-NO2-Ph 140

with C6F5 710

Bu4N+ NO3- 3,5-(NO2)2-Ph 1550 Ballester, P. et al.
J. Am. Chem. Soc. 2013, 135, 83124.