Solutions and Non-Covalent Binding ForcesChapter 3

Molecules stick together using the following forces: dipole-dipole, dipole-induced dipole, hydrogen bond, van der Waals/London, dispersion forces, solvophobic forces, Lewis acid-base interactions, metal coordination, charge transfer interactions.Most common solvents interact with other solvent molecules or solutes using dipole-dipole,hydrogen bonding, and London dispersion forces.

3.1 Solvent and solution properties

Dielectric constants (ε)

3.1.2 Solvent scales- Protic solvent: has a hydrogen atom attached to a heteroatom, such as O, N, or S, and

can form hydrogen bonds with a solute molecule as well as with other solvent molecules.- Aprotic solvent: lacks a hydrogen on a heteroatom, and therefore cannot act as a donor.- A polar solvent can be described as a solvent that can solubilize salts or molecules with

large permanent dipoles, while a nonpolar solvent is one that does not.

- a constant to determine whether a solvent is polar or nonpolar, with higher ε values reflecting greater polarity.

- is measured by determining the effect of an intervening solvent on the electric field between two oppositely charged plates.

- Large molecular dipoles, large molecular polarizabilities, and hydrogen bonding sites on the solvent molecules combine to give large dielectric constants.

- ε = εμ/εo; defined as the ratio of the permittivity of the medium (εμ) to the permittivity of a vacuum (εo).

- This constant gives insights into how well the solvent screen electrostatic forces.- solvents with high dielectric constants more efficiently screen the attractive or

repulsive forces between ions and the ends of dipoles.

Large dipole, hydrogen bonding capability and more polarizable than water

3.1.3 Solubility

3.2.1 Ion pairing interactions

3.2 Binding forcesIntermolecular and intramolecular interactions

Electrostatic interactions

Coulomb’s law

E: attractive or repulsive potential E between two charges q1 and q2

ε: dielectric constant of the mediumr: distance

rq2q1

ε

Salt bridges: an ion pair between two side chains of a protein

Asp or Glu ….. Lys or Argup to 3 kcal/mol

0-2 kcal/mol

3.2.2 Electrostatic interactions involving dipoles

Ion-dipole interactions

μ = q1l

Solvation of ionsLi+ > Na+ > K+ > Rb+

The smaller the ion, the greater the hydration energy. This trend is an indication of a largely electrostatic effect.

Dipole-dipole interactions

3.2.3 Hydrogen bonding

Hydrogen bond is described as a Coulombic interaction between a polar donor (Dnδ--HDδ+)And an acceptor atom (:Acδ-).Since the hydrogen bond is a simple Coulombic interaction, any partial negative charge canAccept a hydrogen bond, not just electronegative atoms, but even π systems.

Unusual hydrogen bond acceptor

GeometrySince electrostatic considerations dominate for most hydrogen bonds, the geometry of the Hydrogen bond is not a major contributing factor to strength. Still, the optimal geometry has a collinear arrangement of the three atoms involved, even though significant deviations from linearity can be tolerated.

Three-center hydrogen bondsor bifurcated (두갈래로갈라진) HB

Strengths of normal HBsVery strong HBs: 15-40 kcal/molModerate HBs: 5-14 kcal/molWeak HBs: 0-4 kcal/mol (most common HBs)- Consistent with the elctrostatic model, there is a general trend that the hydrogen bonds

is stronger if one or both of the partners is charged, meaning that the electrostatic nature significantly increases due to large Coulombic attraction.

1. Solvation effects

Solvent: the factor that most influences the strength of a HB because the donor and acceptor are solvated prior to formation of Dn-H--:Ac hydrogen bond.

HB strength for Gas phase or nonpolar solvents: 5-10 kcal/molHB strength in the interior of a protein that is dissolved in water: 0.5-1.5 kcal/molHB strength not in the interior of a protein: ~0 kcal/molWhen one of the components, either the donor or acceptor, is charged,

HB strength: 4.0-4.5 kcal/mol.

2. Electronegativity effects

HF > HCl > HBr > HI (depending on charge on hydrogen)CF3CO2H > CCl3CO2H > CBr2CO2H > CI3CO2H (the same atom -> depending on acidity)

For the donors

For the acceptorsH2O > H3N > HS > H3P Electronegativity increases the δ- on the atom, which is good for hydrogen bonding, but it makes the element less willing to share its electrons, which is bad for hydrogen bonding. -> Bonds to F are quite polar, but F is a very poor hydrogen bond acceptor (i.e.Poor electron donor). Hydrogen bonds involving F as the acceptor are actually rare.The poor hydrogen bonding see with S and P is likely due to the very diffuse nature of the lone pairs in third row elements.

3. Resonance assisted HBsc

4. Polarization enhanced HBs (also known as cooperative HBs)

Cyclic trimer: 5.6 kcal/molCyclic pentamer: 10.6 kcal/molCyclic hexamer: 10.8 kcal/mol

5. Secondary interactions in hydrogen bonding systems

6. Cooperativity in HBs

The repeating structure of the a-helix reinforces itself. Once a few hydrogen bonds areFormed, the system naturally propagates andeach hydrogen bond reinforces the next.This can be viewed as an entropic effect. The first few HBs pay most of the entropic cost, Making it more and more favorable to continue the stretch of hydrogen bonding.

Vibrational properties of HBs

significant energy barrier

Normal HBs Low barrier HBs no barrier HBs

Short strong HBs

pKa 12.1 16.1 13.9

Steric compression

Short distance

3.2.4 π effects

Cation-π interactionsPermanent quadrupolemoment

Li+ > Na+ > K+ > Rb+

Quadrupole: is simply two dipoles alignedin such a way that there is no net dipole (if there was a dipole, we’d have a dipole, not a quadrupole).

CH3NH3+….-2OCCH3 (electrostatic interactions):

~120 kcal/mol in the gas phase, <2 kcal/mol in waterCH3NH3

+….benzene (cation-π interactions): ~18 kcal/mol in the gas phase, ~5 kcal/mol in water

In proteins, Lys / Arg interact with Phe / Tyr / Trp

NH3+

CO2-

NH3+

CO2-

OH

NH3+

CO2-

HN

Phe Tyr Trp

+H3N

CO2-

+H3N

NH

CO2-

+H3N

+H2NNH2

Lys Arg

e.g) Nicotine receptor

Acetylcholine (Ach)

NO

OMe

MeMe

Polar-π interactions

Gas phase (binding energy)

1.9 1.4 1.6 kcal/mol

Water binds cations electrostaticallyby aligning its large permanent dipole moment.Benzene binds cations electrostaticallyby aligning its large permanent quadrupolemoment.

CO2-

destabilized

pKa = 6.39

benzoic acidpKa = 4.2

Aromatic-aromatic interactions (π stacking)

Adverse electrostatic interactions

In some more complicated structures the T-shaped geometry cannot be obtained.In these cases, then, it is best to form a displaced or slipped stack. This still aligns regions of positiveelectrostatic potential with regions of negative electrostatic potential.

π Donor-acceptor interactionsA donor-acceptor interaction occurs between any two molecules, or regions of a molecule,where one has a low energy empty orbital (acceptor) and the other a high energy filled orbital (donor). When these two orbitals are aligned properly, some extent of charge transfercan occur from the donor to the acceptor. This is stabilizing interaction.

electron poor

electron rich

Generally, a large extent of charge transfer leads to colors. No new bonds are formed, however, as each partner can be re-isolated intact. The color arises from an absorbance of light that promotes an electron from the donor to the acceptor – the full charge transfer occurs in the excited state, while only orbital mixing occurs in the ground state.

Charge transfer complexes

3.2.6 The hydrophobic effect

- This effect drives the association of organics together in water.- Hydrocarbons and related organic compounds are insoluble in water.- This effect is single most important component in biological molecular recognition.- It is the strongest contributor to protein folding, membrane formation, and in most cases, small molecule binding by receptors in water.

Aggregation of organics

The hydrophobicity of organic groups can be measured by the partitioning of organic molecules between a nonpolar solvent, typically n-octanol, and water.

hydrophobicity constant = Po: the partitioning of an organic molecule

between octanol and water without RP : the partitioning of an organic molecule

between octanol and water with R attached

For large molecules that can experience more substantial changes in surface area as a result of conformational changes, the effect could be quite large. -> the primary driving force for protein folding

gas phase, 70:30 (anti:gauche)liquid butane in water, 55:45 (anti:gauche)

More compact

hydrophobicamphiphilic

hydrophilicmicelle: a rough spherical structure

Critical micelle concentration: a concentration where micelle is formed

Vesicles: bilayers

phospholipids

The origin of the hydrophobic effect

hydrocarbon

While ice has a low enthalpy thanwater due to more hydrogen bonds, it is entropically disfavored due to the increase in order.Water in contact with an organicmolecule loses favorable water-water contacts. To compensate, it strengthens its remaining water-water contacts, making them more ice-like. The local water structure becomes more rigid, and the strengths and number of individual water HBscan compensate for the lost HBsdue to the presence of the cavity created by the orgnic entity, and may even be entthalpically favorable. Due to the increased ice-like nature of the waters around the organic, the entropy has significantly decreased.Dimer structure; when the two hydrophobic molecules associate, the hydrocarbon surface area exposed to water decreases, diminishing the amount of ice-like water.

-> unfavorable enthalpy change or a close-to-zero enthalpy change. But entropically favorable. The net effect is that the TΔSo term outweighs the ΔHo term, producing a favorable ΔGo. Hydrophobic association is entropy driven.