Transcript Document

Hydrogen bonding
and weak
interactions
“Symmetry E70
(Butterflies)”
by M.C. Escher - 1948
“Symmetry E72
(Fish and Boats)”
by M.C. Escher - 1949
Factors important in solid state pharmaceutical
chemistry
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As shown in the “Patenting” lecture, characterizing and
understanding the structure of the solid state is very
important when improving the performance of a drug as
well as other materials
In order to do this at least the following has to be
understood:
• Materials (and drugs) can often exist in many forms including
polymorphs, solvates and amorphous materials. Understanding
why and learning how to control these is very important.
• Various forms of a material/drug may interconvert under
various conditions. Even air humidity may drive the conversion
process to another more stable (perhaps patented) form.
• Once a form of a material/drug has been chosen methods for
analysis and control of the form have to be established.
Intermolecular Forces – forces keeping
crystals together
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Ion-ion interactions – obvious – going to mostly ignore as it
was covered in 2nd year
Ion-dipole – between an ion and an opposite partial charge
on a molecule
Dipole-dipole – between the electric dipoles of polar
molecules
Induced-dipole – between a polar molecule and neighboring
polarizable molecule
Dispersion forces (London forces) – arises from fluctuations
in electron distributions with molecules
H-bonding – special case formed by a H-atom lying
between two strongly electronegative atoms
Intermolecular Forces contd.
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The strongest interaction listed above is the ion-ion
interaction - very important in minerals
However, the rest are more important in molecular crystals
and in the chemistry of life itself. Examples will be given of
both.
H-bonding is the next most important interaction
Dispersion forces are the next most important when viewed
from the point of view of how much they contribute to the
total lattice energy of a molecular crystal
H-bonding, dipole-dipole and ion-dipole interactions play a
huge role in determining the structure of a material/crystal
– can drive the crystallization process or a protein catalysis
process
Some examples containing
Dipole-dipole and/or dipoleinduced dipole interactions
benzoquinone
O
O
Structure composed of C-H…O stabilized layers of molecules
1,4-anthraquinone
O
O
Each pair of molecules in the structure is stabilized by dipole-induced
dipole interactions between the C=O and benzene ring. This is just
one amongst many other interactions.
p-iodobenzonitrile
N
I
I
N
In this case the N atom induces a dipole on the I atom creating a
favorable interaction. N…I distance 3.18 Å, c.f. VDW contact dist. 3.65 Å.
In an O…Hal or N…Hal interaction the strength of the interaction
increases in the following order Cl<Br<I. Note that the C-Hal…O/N angle
is almost linear.
O
I
O
OCH2CH3
P
C
CH3CH2CH2CH2
* = O…I
# = C-H…π
OCH2CH3
C
I
π...π interactions
Caused by intermolecular
overlapping of p-orbitals in πconjugated systems
Become stronger as the number
of π-electrons increases
Some examples of structures
stabilized by dispersion forces
naphthalene
anthracene
These two structures are stabilized by dispersion forces and not specific
interactions though the structures do have very weak C-H…π interactions
benzene
H-bonding
H-bonding as taught in 1st year
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As typically taught limited to a few elements – N, O and F
forming O-H…O, O-H…N, N-H…F, etc.
This is wrong. Though much weaker between other
elements, even weak H-bonding has a very significant
effect on a crystal structures as well as biological
processes
π
π
Examples of weak H-bonds are C-H…O, C-H… , O-H… ,
C-H…Cl, C-H…N, O-H…Cl, etc.
O
H
O
H
H
O
O
H
H
O
O
H
H
O
O
H
H
O
O
O
CH3
O
So why do 1st year text books insist that Hbonding only occurs between O, N and F?
To get round this issue H-bonds not involving O, N and F as
donor and acceptor are referred to as weak H-bonds
H-bonding and polymorphism in OETCA
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The following example illustrates the influence of weak Hbonding on the structure of several polymorphs of
o-ethoxy-trans-cinnamic acid (OETCA)
O
O
OH
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So far OETCA has been found to form 3 polymorphs (α,
α', and γ) and 2 solvated forms (β)
• A polymorph is a solid crystalline phase of a compound
resulting from two or more different arrangements of
molecules in the solid state - it is restricted to pure
compounds
• Solvates share a similar definition except that a guest
compound (such as a solvent molecule) is included in the
crystal structure
The α polymorph of OETCA
H
O
H
O
O
H
P-1
H
6.69 Å 8.68
Å H 10.01 Å
H
O 67.86º
O
72.01º H 71.46º
O
H
O
a)
b)
O
$$
$$ = C-H…O
** = O-H…O
**
$$
$$
O
OH
OH
**
O
$$
O
The α polymorph of OETCA contd.
Centrosymmetric C-H…π
interactions between
neighboring layers
Layered structure
The γ polymorph of OETCA
C2/c
16.99 Å
90º
5.46 Å
110.85º
23.21 Å
90º
The γ polymorph of OETCA contd.
In this case each OETCA
molecule acts as a C-H…π
interaction donor to one layer
and as an acceptor to another
Acceptor
Herring bone type structure
Donor
The β polymorph of OETCA
In this case each OETCA molecule is H-bonded to another
OETCA molecule to form a dimer which then arranges in such
a way that it surrounds a benzene molecule in a channel
R-3
37.51 Å
90º
37.51 Å
90º
3.93 Å
120º
H-bonding and polymorphism in OETCA
contd.
The H-bonded dimer
is common to all the
polymorphs. The
layered structure is
found in the α, α' and
γ polymorphs. The
difference between
these is subtle and
driven by weak Hbonding and
dispersive forces.
The reliability H-bonding of donors and acceptors
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When a molecule is capable of both intra- and inter-molecular
H-bonding, predicting which will occur is often unreliable
O
O
H
H
O
O
O
O
O
H
CH3
O
CH3
Solid state
Solution
o-methoxybenzoic acid
O
O
O
H
C2H5
Solid state and solution
o-ethoxybenzoic acid
In this case the addition
of a single CH2 changes
the solid state H-bonding
pattern.
Just how does one
predict when this will
happen?
This is currently a huge
problem in SS chemistry.
The reliability H-bonding of donors and acceptors
contd.
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To get around this problem workers in this field have created
tables of reliable and unreliable donors and acceptors
Type
Functional group involved
Reliable donor
-OH, -NH2, -NHR, -CONH2, -CONHR, -COOH
Occasional donor -COH, -XH, -SH, -CH
Reliable acceptor -COOH, -CONHCO-, -NHCONH-, -CON<,
>P=O, >S=O, -OH
Occasional
acceptor
>O, -NO2, -CN, -CO, -COOR, -N<, -Cl
The reliability H-bonding of donors and acceptors
contd.
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In addition, some rules governing H-bonding in solids have
been proposed
These rely on the classification of H-bond donors and
acceptors into reliable and unreliable
Using the above the following 3 rules have been devised:
1.
All (or as many as possible) good proton donors and acceptors
are used in H-bonding
2.
6-membered intramolecular H-bond rings form in preference to
intermolecular H-bonds
3.
The best proton acceptors and donors remaining after the
formation of an intramolecular H-bond will form intermolecular
H-bonds
O
O
H
H
O
O
O
O
O
H
CH3
O
CH3
Solid state
Therefore according to
the above rules the
intramolecular H-bond is
the one usually
favoured
Solution
o-methoxybenzoic acid
O
O
O
H
C2H5
Solid state and solution
o-ethoxybenzoic acid
However, these rules
often break down for
large molecules
H-bonding in two very similar molecules
O
OH
HO
O
NB!! All (or as many as
possible) good proton
donors and acceptors
are used in H-bonding
O
NH2
H2N
O
What do carboxylic acids do in the solid state?
O
O
O
H O
H
Synplanar
O
O H
Antiplanar
Carboxylic acid groups occur in two distinct
conformations, synplanar and antiplanar.
The syn conformation is more stable by
about 10 kJ/mol and as a consequence Hbond patterns based on it are more stable.
H O
O
O
O
O
H
Dimer
O
O
O
O
O
O H
O
O H
Syn,syn-Catemer
H
H
O
H O
O H
O
O
O
O H
H
anti,anti-Catemer
syn,anti-Catemer
Graph Set Notation
Graph set notation examples
A pattern composed of only one type of H-bond is referred to as a
Motif - each of the above is a motif
Graph set notation
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Used to describe H-bonding patterns in crystal structures
Reasonable to expect that the more H-bond donors and
acceptors a molecule has the greater the variety of
structures that it can form, since they might be expected to
combine in a multitude of different ways.
However, some donor-acceptor combinations are more
favorable than others
• Strong H-donors preferentially H-bond with strong H-acceptors
• This is a little like the soft/hard ligand and metal concept in
OM chemistry
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Relies on the fact that H-bonds are both very strong and
directional. As a consequence patterns between functional
groups tend to be consistent.
Graph set notation contd.
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Preference for some H-bond patterns leads to H-bond
patterns being retained in the various polymorphs of a
specific compound rather than the creation of a variety of
hydrogen bond patterns. (Look at the OETCA example)
The understanding and characterization of hydrogen bonds
is therefore very important in order to understand their
effect on crystal structure - allows one to have some idea of
what kind of interactions will occur between molecules of a
given compound.
Graph set notation has been introduced in order to simplify
this process.
Graph set notation contd.
• The graph set approach to the analysis of H-bond patterns
allows the most complicated networks can be reduced to
four basic patterns, each specified by a designator:
•
•
•
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chains (C)
rings (R)
intramolecular hydrogen bonded patterns (S) (self)
other finite patterns (D) (discrete)
• Graph set designators are given in the form Gab(n)
•
•
•
•
G is one of the four possible designators (C, S, D and R)
a gives the number of H-bond acceptors
b gives the number of H-bond donors
n gives the number of atoms in the pattern and is called the
degree of the pattern and is given in parenthesis
Graph set notation examples
A pattern composed of only one type of H-bond is referred to as a
Motif - each of the above is a motif
Extending Graph set notation – “levels”
• To simplify the analysis of complex H-bond networks the
network is broken down into its component patterns and
given as a list of motifs
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This list of component motifs is referred to as the unitary or
first level graph set and is noted as N1
These unitary graph sets can then be combined to give
higher level graph sets
A network formed by two different H-bonds is referred to as
a binary level graph set (noted as N2) while a network
composed of three different hydrogen bonds is referred to
as a tertiary level graph set (noted as N3), i.e. the more
component hydrogen bonds in a specific pattern the higher
the level of the graph set
Extending Graph set notation – “levels”