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INTRODUCTION
HYDROGEN BONDING
Hydrogen bonding is the most reliable design element in the non-covalent assembly of
molecules with donor and acceptor functionalities, and as such it is the most important
interaction in the areas of supramolecular chemistry, crystal engineering, material science and
biological recognition1-3. The hydrogen bonding interaction plays an important role in
stabilizing supramolecular aggregates4,5 and also in determining the structure and stability of
the 3-D structure adopted by macromolecules like proteins and nucleic acids.
Hydrogen bonds are primarily electrostatic and are formed with both strong and weak
donors and acceptors. A hydrogen bond is an interaction between a proton donor group D-H
and a proton acceptor atom A, the D-H…A interaction being called as a hydrogen bond.
Generally, a hydrogen bond can be characterized as a proton shared by two lone electron pairs.
Hydrogen bond energies range from about 15-40 kcal/mol for strong bonds, 4-15 kcal/mol for
moderate bonds and 1-4 kcal/mol for weak bonds4. The distance between the H and A in a
hydrogen bond is less than the sum of their respective vander Waals radii6. Hydrogen bonds
can be experimentally investigated by a variety of experimental techniques, such as Neutron
diffraction, X-ray diffraction, NMR, IR and other spectroscopic techniques. The different types
of hydrogen bonds are shown in Scheme 1. Some examples of complementary hydrogen
bonded interactions are shown in Scheme 2.
Etter and coworkers7,8 have studied the preferential hydrogen bond patterns in organic crystals
and have presented the following rules.
1.
All good proton donors and acceptors are involved in hydrogen bonding.
2.
Six-membered ring intramolecular hydrogen bonds form in preference to
intermolecular hydrogen bonds.
3.
The best proton donor and acceptor remaining after intramolecular hydrogen
bond formation will form intermolecular hydrogen bonds.
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Describing Hydrogen bonded motifs using Graph-sets:
Etter, Bernstein and coworkers have introduced a language based upon graph-theory for
describing and analyzing hydrogen bond networks in three-dimensional solids9,10. A generic
graph-set descriptor is
G ad (n) where,
G = Graph set designator C/R/D/S
d = Number of donor atoms
a = Number of acceptor atoms
n = Total number of atoms present in the hydrogen bonded motif.
All hydrogen bonding patterns can be described in terms of chains (C), rings (R) dimer
(D) and intramolecular hydrogen bonds (S). The graph set notations for some hydrogenbonded motifs are shown in Scheme 3.
SUPRAMOLECULAR CHEMISTRY AND CRYSTAL ENGINEERING
Supramolecular chemistry and crystal engineering are closely related fields. Both
involve the non-covalent interactions as their basis and have expanded the frontiers of chemical
science dealing with many physical and biological phenomena.
In recent years supramolecular chemistry has established itself as one of the most active
fields of science. Pioneering work in this field have been done by Charles Pedersen, Donald
Cram and Jean-Marie Lehn on cryptands and crown ethers in the area of host-guest
chemistry, winning them the 1987 Nobel prize for chemistry.
Supramolecular chemistry has been defined by Lehn in 1969 as
Chemistry of molecular assemblies and of the intermolecular bond’, ‘chemistry beyond
the molecule’ and ‘the chemistry of the non-covalent bond’
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In contrast to molecular chemistry, which is predominantly based upon the covalent
bonding of atoms, supramolecular chemistry is based upon intermolecular interactions
(hydrogen bonding, - stacking, van der Waals interactions), where the building blocks are
reversibly held by intermolecular forces resulting in non-covalent assemblies. The term ‘noncovalent’ contains an enormous range of intermolecular interactions, which however originate
from only a few attractive and repulsive forces.
These are represented in the order of
decreasing strength.
1. Electrostatic interactions (ie) ion-ion, ion-dipole and dipole-dipole interactions and
coordinative bonding.
2. Hydrogen bonding
3. - stacking
4. van der Waals forces
Among the non-covalent interactions, the hydrogen bonds play a crucial role in
supramolecular organization. The role of hydrogen bonding in determining the packing motifs
of molecules in crystals requires recognition controlled self-assembly of complementary
molecules, and hydrogen bonding has been largely exploited for this purpose11,12 .The study of
non-covalent interactions is crucial to understanding many biological processes. These
interactions also play a very important role in the flexibility of the macromolecules and their
interactions.
Crystal Engineering has been defined by -G.M. J. Schmidt 13 as,
“It is the understanding of intermolecular interactions in the context of crystal
packing and in the utilization of such understanding in the design of new solids with
desirable physical and chemical properties”
What best the chemists can do is to find recurring packing patterns adopted by certain
functional groups and rely on the robustness of such motifs to create new solids structures. The
repetitive units of these small sized hydrogen bonded motifs are supramolecular synthons and
they hold the key to crystal engineering.
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Applications
Supramolecular chemistry and molecular self-assembly processes in particular have
been applied to the development of new materials. Molecular self-assembly allows the
construction of larger structures such as micelles, membranes, vesicles, liquid crystals, which
are important to crystal engineering. The properties are important in both material science
(magnetism, conductivity, catalysis, molecular sensors, molecular switches and non-linear
optics) and biology (protein-receptor binding, protein folding and drug design).
This thesis deals with the crystal structures of N-heterocycles namely some
aminopyrimidine and triazine complexes.
The objective of the work is to study the
conformations of these molecules and hydrogen bonding patterns. The results have been
compared with related systems to understand their biological and supramolecular implications.
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PART – I
Aminopyrimidine-carboxylate/ sulfate/co-crystals
Introduction
Nitrogen is the second most abundant macronutrient in cellular organisms, where it is
found in major macromolecules (proteins and nucleic acids), primary metabolites (ATP and
NADH), and secondary metabolites such as antibiotics. Over 50,000 organonitrogen
compounds are biosynthesized by plants and microbes14. Many of these compounds are Nheterocycles, ring structures containing one or more nitrogen atoms in the rings. Pyrimidine
and aminopyrimidines are heterocyclic aromatic organic compounds, occur in nature as
components of nucleic acid (cytosine, uracil and thymine). They are also the major components
of many drugs15-17. Some of the pyrimidine nucleobases and their derivatives used as drugs are
schematically represented in Figure 1.
The hydrogen bonding patterns including base pairing formed by the aminopyrimidines
are important in nucleic acid structures and their functions. For genetic information transfer,
proper base pairing among the nucleobases is essential. In 2-aminopyrimidine, base pairing
occurs through a pair of N-H…N hydrogen bonds, whereas in protonated 2, 4diaminopyrimidines two types [N2-H…N3 and N4-H…N3] of base pairing are observed. The
base pairing patterns and the hydrogen bonded motifs are shown in Figure 2.
The carboxyl group and also the carboxylate anion can involve in hydrogen bonding
interactions with aminopyrimidines. These interactions play a vital role in protein-nucleic acid
interactions15 and such interactions are also involved in drug-protein recognition processes. The
pyrimidine moiety of a drug form hydrogen bonds with the carboxyl group of the protein.
Many organic molecular motifs form the essential structural components of biological systems
and various drugs18. The three dimensional structures and the interactions of bioorganic motifs
are responsible for the existence of the biological systems and are very useful in bimolecular
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recognition18,19. Different types of aminopyrimidine-carboxylate interactions are shown in
Figure 3.
It has been observed that in all the aminopyrimidine carboxylate/co-crystal complexes,
the fork-like [Motif I and Motif II] interaction between the carboxylic acid/carboxyl groups
with the aminopyrimidine moiety forms as essential feature of supramolecular architecture. In
order to study the variation of the supramolecular organisation depending upon the nature of
the side chain R, attached to the COOH group, a number of carboxylic acids with different
modifications in the side chain have been tried and an attempt has been made to study their
effect on the hydrogen-bonded supramolecular motifs which result in the supramolecular
organisation.
Motif I and Motif II are among the 24-most frequently observed bimolecular cyclic
hydrogen bonded motif in organic crystal structures20. The Motif I [R22(8)] can also be
generated using sulfate, sulfonate, nitrate, fluoroborate and perchlorate as suitable anions. The
Motif I self assembles in combination with various hydrogen bonding patterns to form
quadruple hydrogen bonding motifs DDAA (Motif VIII) array (D = hydrogen bond donor & A
= hydrogen bond acceptor) and DADA (Motif IX). Motif VIII and IX are commonly recurring
hydrogen-bonding patterns in diaminopyrimidine salts (Figure 4).
Earlier, the 2-aminopyrimidine-carboxyl group interactions21,22 and triaminopyrimidine
(2,4,6-triaminopyrimidine)-carboxylate interactions have been reported in literature23. The
diaminopyrimidines-PMN[2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine],
TMP[2,4-
diamino-5-(3’,4’,5’-trimethoxybenzyl)pyrimidine] and aminopyrimidines-AMPY[2-amino4,6-dimethylpyrimidine]and MEOPY[2-amino-4,6-dimethoxypyrimidine] have been chosen
for the present study [Figures 5a-5d].