A quick survey through
non-covalent interactions
Dr. Frank Biedermann, Institut for Nanotechnologie (INT)
E-Mail: frank.biedermann@kit.edu
1
Definition
• F. Vögtle: „In contrast to molecular chemistry, which is
predominantly based upon the covalent bonding of atoms,
supramolecular chemistry is based upon intermolecular interactions,
i.e. on the association of two or more building blocks, which are held
together by intermolecular bond”
• J. M. Lehn: „Supramolecular chemistry is the chemistry of the
intermolecular bond, covering the structures and functions of the
entities formed by the association of two or more chemical species“
• J.M.L.: “Supermolecules” are to molecules and the intermolecular
bond what molecules are to atoms and the covalent bond”
2
moleculare vs. Supramoleculare Chemie
Schema J.-M. Lehn 3
History
• 1873: Intermolecular Interactions, Johannes D. van the Waals
• 1891: Cyclodextrin-Complexes, A. Villiers
• 1893: Koordination Chemistry, Alfred Werner
• 1894: Lock-and-Key-Prinzip, Emil Fischer
• 1906: Receptor Concept, Paul Ehrlich
• 1937: „Übermolekül“ through Self-Assembly, K. L. Wolf
• 1953: DNA Structure, James Watson & Francis Crick (& Rosalind Franklin)
• 1967: Crown ether, Charles Pederson
• 1969: Cryptands, Jean-Marie Lehn
• 1973: Pre-organisation, Donald Cram
• 1978: Phrase „Supramolecular Chemistry“, Jean-Marie Lehn
• ……..
4
History: Nobel Prize in Chemistry 1987
Charles J. Pedersen
Dupont, Wilmington
Jean-Marie Lehn
Strasbourg
Donald J. Cram
Los Angeles
„for their development and use of molecules with
structure-specific interactions of high selectivity “ 5
History: Nobel Prize in Chemistry 2016
Fraser Stoddart
Northwestern University
Ben L. Feringa
Groningen
Jean-Pierre Sauvage
Strasbourg
„for the design and synthesis of molecular machines“
6
Types of Non-Covalent Interactions
Ion-Ion Int. Ion-Dipol Int.
Dipol-Dipol Int. H-Bonds cation- Int.
7
Types of Non-covalent Interactions
--Interaction
Sandwich T-Form Slipped arrangement
Halogen-Bond Dispersions Int. (van the Waals Bond)
8
0 600500400300200100
ion-ion interactionsa
covalent bonda
van der Waals forces
cation-p interactions
hydrogen bonding
dipole-dipole interactions
ion-dipole interactionsa
kJmol-1
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Types of Non-covalent Interactions
9
Ion-Ion Interactions
Molecular
capsules
DNA-wrapping and Gen-Regulation through Histones
10
Ionic Interactions
𝐸 =
𝑄1 𝑄2
4𝜋𝜀𝑟
Elektrostatic Potential
Repulsive Int.
𝐸 =
𝐵
𝑟 𝑛
Salt
lattice
calculated
lattice energy
(kJ/mol)
experiment.
lattice energy
(kJ/mol)
NaCl 756 787
LiF 1007 1046
CaCl2 2170 2255
Born–Landé equation
For NaCl lattice:
Madelung const. = 1,748
11
Fuoss Equation for Ion Pairs in Solution
Test for CaSO4
radius(Ca2+) = 1.14 Å
radius(SO4
2−) = 1.49 Å
a ≈ 2.63 Å
with zA =zB = 2
and ε = 80.4 for water
K = 1690 M−1
with ∆G = −RT∙ln K
∆G = −18.4 kJ/mol
and
∆H = 9.6 kJ/mol (endotherm)
T∆S = −28.0 kJ/mol
Comparison to experiments?
12
Ionic Interaction in Solution
solvent-separated
ion pair
contact ion pairsolvent-bridged
ion pair
13
Experimental Results for Ionic-Interactions
❑ Good correlation between ∆G and ∙ zA ∙ zB,
for 200 ion pairs in water
❑ Agreement with Fuoss Equation
❑ Lowering of the ionic bond
strength upon salt addition
❑ Agreement with
Debye-Hückel Theory
14
Problems with Theoretical Models
for Ion Pairing
Theory predicts a smaller K with
a larger distance.
Experimentally, the opposite was
found!
Fuoss theory (full equation) predicts K-Minimum at a = 2.4 ∙ zA ∙ zB . This was never
experimentally found.
Models do not consider specific solvation structures of the ions, particularly small and
highly charged ones.
15
Experimental Findings for Ionic Interactions:
Organic Ions
often additivity observed
∆Gtotal = N ∙ ∆GInkrement
Experimental Trends:
❑ Per ion pair, that forms,
ca. 2-8 kJ/mol (often ~5 kJ/mol)
gain in ∆G in water.
❑ Distance dependency
❑ Ion pair-formation in water mostly
entropically driven, enthalpy ~ 0.
16
Hydrogen Bonds
17
Pauling’s Definition (1939)
Under certain conditions an atom of hydrogen is attracted by rather
strong forces to two atoms instead of only one, so that it may be
considered to be acting as a bond between them.
Steiner–Saenger Defintion
Any cohesive interaction X–H•••A where H carries a positive and A
a negative (partial or full) charge and the charge on X is more negative
than on H.
O–H···O− O–H···O N–H···O
O–H∙∙∙π N–H∙∙∙π C–H···O
Os–H···O C–H···Ni C–H∙∙∙π
Weak Hydrogen Bonds
18
+ H3C-NO2
C-H als H-bond-Donor
Desiraju–Steiner definition (1999)
The weak hydrogen bond is an interaction X–H···A wherein a
hydrogen atom forms a bond between two structural moieties X
and A, of which one or even both are of moderate to low
electronegativity
Hydrogen Bonds
19
New IUPAC Definition:
“The hydrogen bond is an attractive interaction between a hydrogen atom from
a molecule or a molecular fragment X–H in which X is more electronegative
than H, and an atom or a group of atoms in the same or a different molecule, in
which there is evidence of bond formation.”
Nat. Commun. 2014, Article # 3931
„Visualization“ of H-bonds by Dynamic Force MicroscopyAmid-Dimer in CCl4H-bond-network of water
Influence of Hydrogen Bonds on the Boiling Point
20
Classification of Hydrogen Bonds
21
From Book: Supramolecular Chemistry, Wiley
linear bent
bifurcated
Distance-Energy Relation of Hydrogen Bonds
22
Mesomerie-stabilisierte Hydrogen Bonds
23
Mesomeric structures with charges
=> Stronger H-bonds
Correlation of the Bond Energies
24
lg K = 7.354 α2
Hβ2
H - 1.094
Empirical equation for 1:1 associations complexes with H-bonds in CCl4
measured for >1000 pairs,
R2 = 0.9912
Abraham
e.g. with α2
H = 0.57 for 4-CH3-Ph-OH and β2
H = 0.69 for Ph-CO-NR'R'‘
∆Gcalc = 10 kJ/mol in CCl4 (Experiment: 11 kJ/mol)
e.g. with α2
H = 0.57 for 4-CH3-Ph-OH and β2
H = 0.52 for Pyridin
∆Gcalc = 6 kJ/mol in CCl4 (Experiment: 9 kJ/mol)
Intramolecular Hydrogen Bonds
25
Intramolecular H-bonds increase the rigidity of molecule
„Proton sponges“
Graphical depiction with errors. These are linear bonds!
Ricolinic acid
Tsiede = 245°C
Comparison: Oelic acid Tsiede = 360°C
What is wrong here?
Self-assembly through Hydrogen Bonds
26
Cellulose
Kevlar
Nylon6,6
27
Secondary Interactions for Hydrogen Bonds
K = 102 M−1
K = 104 M−1 K > 105 M−1in CDCl3
attractive repulsive
Double Mutant Analysis
28
Hydrogen Bonds in Membrane Proteins
29
Nature 2008, 453, 1266.
Sometimes hydrogen bonds stabilize, and sometimes destabilize protein folding!
(On average only 3 kJ/mol stabilisation per H-bond pair)
Streptavidin-Biotin: Biological Record-affinity
30
Synthetisches Analoga
Ka = 9∙103 M−1 in CHCl3
−∆G = 22.6 kJ/mol
Ka = 3∙1013 M−1 in H2O
−∆G = 76.4 kJ/mol
Biotin
(Vitamin B7)
Anion-Binding through Hydrogen Bonds
in DMSO
+ 0.5% water
31
in CHCl3
Anion-Binding through Hydrogen Bonds
32
in CH3CN
The larger the negative charge
density of the anion, the stronger the
anion binding.
Preorganisation leads to
stronger binding receptors
33
Record Affinities for „classical“ H-Bond Anion Binding
in CHCl3
in CH3CN
Record Affinities for „classical“ H-Bond Anion Binding
34
Org. & Biomol. Chem.
2014, 12, 8851-8860.
35
Jacobsen group: J. Am. Chem. Soc., 2007, 129 (44), pp 13404–13405
Chirale Anion-Bondskatalyse
Dipole - Dipole Interactions
36
Energy ~ 5 bis 50 kJ/mol
Aceton: for 0.5 nm distance
E ~ 2 kJ/mol in CH3Cl
Dispersion Interactions
37
Ar ••• Ar
𝐸𝐴𝐵
𝑑𝑖𝑠𝑝
= −
3
2
𝐼𝐴 𝐼 𝐵
𝐼𝐴 +𝐼 𝐵
𝛼 𝐴 𝛼 𝐵
𝑅6
London-Dispersion-Formula:
London
Attraction
Pauli-
Repulsion
Dispersions Energies are important!
Atom- or Molecule pair Fraction of Edisp from Etotal (%)
Ne-Ne 100
CH4-CH4 100
HCl-HCl 86
HBr-HBr 96
HI-HI 99
CH3Cl-CH3Cl 68
NH3-NH3 57
H2O-H2O 24
38
Comparison:
Sublimation enthalpy of iodine (I2) = 62 kJ/mol.
Sublimation enthalpy of water ice = 52 kJ/mol.
Dispersions Interations in Organic Chemistry
Nature 2011, 477, 308-311.
with Disp.
without Disp
“Normal” C-C-Bond:
BDE: 350 kJ/mol = 83 kcal/mol
d = 1.54 Å
Cation- Interactions
M+ ∆GGasphase (kJ/mol)
Li+
159
Na+
113
K+
79
NH4
+
79
Rb+
67
66 92 133113112
∆Ggas phase (kJ/mol) for Na+-complex
40
Cation- Interactions: Explanation Models
−63 0 63
electrostatic potential (kJ/mol)
Literatur: J. Chem. Theory Comput. 2009, 5, 2301
Recap: Resonance & Hammett constants
electrostatic potential
41
Direct Substituent-Effects instead of Resonance
Literatur: J. Chem. Theory Comput. 2009, 5, 2301
42
66 92 133113112∆Ggas(Exp)
67 91 133113111∆Ggas(Theor-total)
65 75 12311397∆Ggas(Theor-Fragment)
(kJ/mol)
43
Cation- Interactions: Experiment vs Theory
−63 0 63
electrostatic potential (kJ/mol)
Solvent Effects on Cation- Interactions
44
52
26
23
23
33
kJ/mol
M+
In the Gasphase: Li+ > Na+ > K+ > Rb+
water: K+ > Rb+ >> Na+, Li+
45
M+ ∆Ggas(Cation-)
(kJ/mol)
∆Ghydr(Cation)
(kJ/mol)
“∆Gaq(Cation-)”
(kJ/mol)
Li+
159 510 -11
Na+
113 410 -24
K+
79 339 -34
NH4
+
79 335 -33
Rb+
67 318 -39
M+ In the Gas phase: Li+ > Na+ > K+ > Rb+
In water: K+ > Rb+ >> Na+, Li+
Experiment:
Very rough estimation: ∆Gaq(Cation-) ≈ ∆Ggas(Cation-) – x ∙ ∆Ghydr(Cation)
x ≈ Fraction of removed solvent shell. (e.g. 1/3)
Solvent Effects on Cation- Interactions
46
Cation- Interaction vs. H-bonds
kJ/mol
52
26
23
23
525
82
22
9
Cation- interactions often stronger than H-bonds in aqueous media!
47
Systems with Cation- Bonding
Rezeptor −∆G (kJ/mol)
A 10.6
B 13.0
in (CDCl2)2
48
Systems with Cation- Bonding
49
in CDCl3
Hammett-Korrelation
59 113 119118∆Ggas(Theory)
(kJ/mol)
Compare::
Systems with Cation- Bonding
50
Supramolecular Catalysis with Cation- Bonds
J. Am. Chem. Soc. 2010, 132, 5030
51
Science, 1997, 277, 1811
Catalysis with Cation- Bonds in Biology
=> Cation- are important for steroid synthesis!
52
Lys
Arg
Phe
Tyr
Trp
7%
18%
10%
14%
26%
Cation- Bonding is Widely Found
Proc. Natl. Acad. Sci. 1999, 96, 9459
53
Lys248 ••Trp265
in Aldehyd-Oxidoreduktase
(Cation- Energy ca. 37 kJ/mol)
Lys76B ••Trp58B
in Transaldolase B
(18 kJ/mol)
Arg77A ••Trp211A
in OppA
(35 kJ/mol)
Arg1136 ••Trp1175
in Insulin Rezeptor
(28 kJ/mol)
Cation- Bonding in Proteins
54
Spektakuläre Cation- Bondsmotive
Glukoamylase
(totale Cation- Energy ca. 92 kJ/mol) growth hormone receptor)
Emil Fischers Lock and Principle
Cortistatin A Cortistatin A • CDK8 complex 55
Induced-Fit Modell (Daniel E. Koshland)
nsLTP-Protein•Oleate nsLTP-Protein•Stereate 56
The 55% Rule
S. Mecozzi, J. J. Rebek, Chem. Eur. J. 1998, 4, 1016-1022. 57
The 55% Rule
S. Mecozzi, J. J. Rebek, Chem. Eur. J. 1998, 4, 1016-1022.
58
Cucurbit[n]urils as Steroid-Binders
59
J. Am. Chem. Soc., 2016, 138, 13022
1∙107
−52
12
70
Ka (M−1) in H2O
∆H (kJ/mol)
−T∆S (kJ/mol)
Packungskoeff.
2∙107
−38
−4
56
<1000
n.d.
n.d.
73
1∙108
−41
−5
59
Solvent- and Hydrophobic-Effects
60
Konventionelle Sichtweise form hydrophobic effect
61
„Lehrbuch-Bild“ form
hydrophobic effect
http://www.chemgapedia.de/
Charles Tanford
(geb. Tannenbaum)
Walter J. Kauzmann1973
The hydrophobic effect is the observed tendency of nonpolar substances to aggregate in an
aqueous solution and exclude water molecules. The word hydrophobic literally means "waterfearing",
and it describes the segregation of water and nonpolar substances, which maximizes
hydrogen bonding between molecules of water and minimizes the area of contact between water
and nonpolar molecules. In terms of thermodynamics, the hydrophobic effect is the free energy
change of water surrounding a solute A positive free energy change of the surrounding solvent
indicates hydrophobicity, whereas a negative free energy change implies hydrophilicity.
The hydrophobic effect is responsible for the separation of a mixture of oil and water into its two
components. It is also responsible for effects related to biology, including: cell membrane and
vesicle formation, protein folding, insertion of membrane proteins into the nonpolar lipid
environment and protein-small molecule associations. Hence the hydrophobic effect is essential to
life. Substances for which this effect is observed are known as hydrophobes.
Types of the hydrophobic Effect
62
Typical Self-assembled Systems in Water
63
Biedermann, F. (2017) Self-Assembly in Aqueous Media.
In: Atwood, J. L., (ed.) Comprehensive Supramolecular Chemistry II, vol. 1, pp. 241–268. Oxford: Elsevier.
Classical view on the hydrophobic effect
64Chothia, C. Hydrophobic bonding and accessible surface area in proteins. Nature 248, 338-339 (1974).
const ~ 120–200 J mol−1 Å−2
for comparison:
Surface tension of water:
γ = 430 J mol−1 Å −2
Standard-Equation for
the hydrophobic effect
Updated Model for the Classical Hydrophobic Effect
65Nature 2005, 437, (7059), 640-647
Standard-Equation for the hydrophobic
effect reached only at larger length scales
At smaller length scales, the hydrophobic
effect is entropically driven.
At larger length scales, the hydrophobic
effect is enthalpically driven.
Results from Computer-SimulatIons:
Updated Model for the Classical Hydrophobic Effect
66Nature 2012, 491, (7425), 582-585.
water
(sclaed)
water + n-Butanol
(Solute-corrected Spectrum)
HO-virbations
water + n-Butanol
water
Enthalpy-Entropy-Compensation
Protein-unfolding
(Myoglobin)
Neopentane-Transfer:
bulk -> water
Protein-Protein
Association
Annu. Rev. Biophys. 2013. 42:121–42
67
Enthalpy-Entropy-Compensation:
Possible reasons:
1)
Higher Binding-enthalpy (deeper potential) leads to worse entropy
2) Entropy-enthalpy compensation due to special features of water
Annu. Rev. Biophys. 2013. 42:121–42
68
Enthalpy-entropy compensation: Is it real?
„enthalpy-entropy-comp.“
for different
protein-ligand complexes
„enthalpy-entropy comp.“
for measured for identical
system in different labs
coincidental selection of
systems with similar
affinities?
Annu. Rev. Biophys. 2013. 42:121–42
69
The High-energy Water Model for Cavities
70
Angew. Chem. Int. Ed.
2014, 53, 11158
The High-energy Water Model for Cavities
71
n
Angew. Chem. Int. Ed. 2014, 53, 11158
72
Data from:
S. Otto and coworkers,
Chem. Eur. J. 2008, 14, 2153
Review:
F.B. H.-J. Schneider,
Chem. Rev. 2016, 116, 5216
Cavity Water Release as an Enthalpic Driving Force for Host-Guests Binding
Host-guest binding in water is often enthalpically favored but entropically disfavored
with ∆𝑯 ≪ 𝑻∆𝑺
F. Diederich and coworkers, J. Am. Chem. Soc. 1990, 112, 339 & J. Am. Chem. Soc. 1991, 113, 5420
Ultra stable Host-Guest Complexes in Water
73
Isothermal Titration Calorimetry (ITC)
Measurement of K, ∆H, T∆S and
the stoichiometry.
74
Bambus[6]uril
Biotin[6]uril
• ∆H << 0 and −T∆S < 0 for alle halogenides in water
• for complexation of Br− & I− through Bambus[6]uril: ∆H(water) < ∆H(CHCl3)
M. A. Yawer, ... V. Sindelar,
Angew. Chem. Int. Ed.
2015, 54, 276
Ka(Iodid) = 2•106 M−1
∆H = −81 kJ/mol
Ka(Iodid) = 5•103 M−1
∆H = −43 kJ/mol
M. Lisbjerg, ... M. Pittelkow,
Org. Biomol. Chem. 2015,
13, 369-373.
Review:
F.B. H.-J. Schneider,
Chem. Rev. 2016, 116, 5216
Ultra stable Host-Guest Complexes in Water
Enthalpy-entropy-Kompensation for Host-Guest Systems
HIV-1 Protease
Inhibitora
Trypsin
Inhibitors
Trypsin
Inhibitors 75
Cooperativity through hydrophobic effect(?)
Hill-coeffizient n: 3.2
76
Reminder: Hill-Equation
Self-Assembly of Surfactants
77
Packing Parameter =
𝑣
𝑎 𝑜∙𝑙 𝑐
Note!
a0 ia only an effective size, that also
depends on charge and other factors
Langmuir 2002, 18, (1), 31-38
Self-assembly of Tensiden
78
∆𝐺 𝑀
0
= 𝑅𝑇
1
𝑗
+ 𝛽
𝑖
𝑗
𝑧 𝑠
𝑧 𝑐
ln CMC +𝑅𝑇
𝑖
𝑗
𝑧 𝑠
𝑧 𝑐
𝛽 ln
𝑖
𝑗
𝑧 𝑠
𝑧 𝑐
−
ln 𝑗
𝑗
∆𝐺 𝑀
0
≈ 𝑅𝑇
1
𝑗
+ 𝛽
𝑖
𝑗
𝑧 𝑠
𝑧 𝑐
ln CMC (eq. 2)
Langmuir 1996, 12, (5), 1208-1211
Pharmaceutical drugs as pollutants in water
Diclofenac Bezafibrate Carbamazepine
Iopromide
Source: World Health Organization: Pharmaceuticals in Drinking Water (2012)
Drug concentration in fresh water (ng/L)
350150
17α-Ethinylestradiol
25
100 5
Host-Guest-Based Water Purification
Dichtel group (USA), Nature, 2015, 529, 190–194