الفهرس 
Chapter1 : IntroductionOnly 14 pages are availabe for public view
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Abstract
This thesis is concerned with studying theoretically the tautomeric
equilibrium of uracil analogue by means of high-accuracy ab initio and DFT
levels of theory; namely CBS-QB3 and B3LYP/6-31+G (d,p) respectively.
The main objective of the study was to introduce insights into structure and
stability of the novel compound AZU azulene based uracil analogue and its
possible tautomers for potential biological and biochemical applications.
The thesis consists of three chapters organized as follows:
Chapter 1 presents a general introduction of the concept of tautomerism as
a special kind of isomerism. Moreover, types of tautomerism
occurred in organic compounds were discussed. Afterwards, we
introduced, in brief, the history of DNA and RNA structures and
functions. Furthermore, introduction on nucleic acid bases are
also introduced. We have concentrated mainly on uracil and it is
modification or fused uracil as well as introducing its chemistry
and applications, especially in the field of medicines. Finally, we
described the new analogue which we are interested in and
mentioned what this study attempts to do. This chapter was ended
by citing of our objective.
Chapter 2 gives a short background about the quantum chemical
calculations and a detail description of the procedures used
throughout this work. Geometry optimizations have been
performed at the B3LYP/6-31+G (d,p) level of theory. After that,
we have indicated explicitly the methods that we have used for
performing geometry optimizations, frequency and solvation. For
all stationary points we have carried out frequency calculations at
the same level to characterize their nature as minima or transition
states and to correct energies for zero-point energy and thermal
contributions. Ab initio multilevel (CBS-QB3) procedure have
also been used for further refinement of the energy values.
Chapter 3 was devoted to discuss the results of our study. We can
summarize our findings as follows:
•In part one, we studied the molecular structures and relative
stabilities of 12 structures which are considered tautomers and
rotamers of uracil analogue. First, the structural parameters of AZU
have been compared with these of the parent uracil. There is a very
good agreement between our calculated geometries for uracil and it is
analogue which gives us a confidence on the structures of the system
where there is a lack of experimental data. The comparison has been
built on the structures obtained by the B3LYP/6-31+G (d, p) level of
theory.
A detailed discussion has been made to describe the geometrical
changes that accompany the enolization processes, i.e. the transformation of
the di-keto isomer to keto-enol and/or di-enol ones. After that, the stability
order based on the relative energies of the investigated tautomers/rotamers
was studied according to the two employing levels of theory. The results
reveal that the di-keto isomer, AZU1, is the most stable one among the
investigated 12 tautomers of uracil analogue according to the two levels in
gas and water. All of two levels indicate that dioxo AZU1 and oxo-hydroxy
AZU4 and di hydroxyl AZU10 are the most stable species in gas phase.
Furthermore, the effect of solvent has also been studied and the results
show that the aqueous medium increases the stability of AZU tautomers.
The previous observation has been supported by studying the dipole
moments of the tautomers, where we found that, among the 12
tautomers/rotamers, AZU2 has the highest dipole moment value. The charge
distributions within the studied isomer were discussed according to the NBO
calculations. Finally, the tautomeric equilibrium in gas-phase and aqueousphase,
were also been calculated. The results of the discussed parameters
predict the stability of the di-keto tautomer AZU1.
•In part two, the pathways of H-transfer and rotation reactions have
been studied by determining the relevant transition states, calculating
the energy barrier heights for each step and studying the rate constants
values in a range of temperatures (298-340 K) using the transition
state theory (TST) and taking into account two different tunneling
corrections, Wigner and Eckart in gas and solvent case. All the
calculations confirmed that the activation energy of the rotation of
proton is much lower than that of the proton transfer, so we conclude
that the rotation of proton happens easier, faster, and with higher
constant rate than the proton transition. Furthermore, by comparing
the results of previous studies of uracil, we conclude that the
tautomerization process in the compound under study (uracil analogue
AZU) is much easier than in the case of uracil itself. Finally, the
zwitterionic structures of AZU6II, AZU7II, AZU8II, AZU9II,
AZU10II, AZU11II, AZU12II, AZU13II forming by carboproton
transfer from C7 to N1 for the parent tautomers AZU6, AZU7,
AZU8, AZU9, AZU10, AZU11, AZU12, AZU13.
•In the third part, more insights have been put into the protonation O
and N atoms and deprotonation of N-H and O-H bonds in gas phase
for all 12 tautomers of uracil analogue. We conclude that the lowest
value of proton affinity and also the highest value in the deprotonation
enthalpy belongs to AZU1, which indicates the stability of this
isomer. In comparing the earlier results of the uracil, we conclude that
uracil analogue is more basic and more acidic than that of uracil itself.
•In the fourth part, the attention of this part is paid to the highest
occupied molecular orbitals (HOMO) and the lowest unoccupied
molecular orbitals (LUMO) which represents the ability to donate an
electron and to accept an electron respectively which are also named
as frontier molecular orbitals (FMO) to study the structure and
reactivity of molecules. Based on the HOMO and LUMO surfaces,
one can say that the whole planar structure is the active center with
several feasible active sites for the interaction. The chemical hardness
(ɳ), electronic chemical potential (μ), Mulliken electronegativity (),
ionization potential (I) and electron affinity (A) of the tautomers are
also investigated in gas and solvent case. from this part, we conclude
that according to the energy of the molecular orbitals, we find that the
most stable and the most hardness isomer is AZU1. The most reactive
and the most softness isomer is AZU2 which is the most unstable
isomers according to total energy.
•We conclude from our previous study that the process of proton
transfer of the azulene compound is easier to occur than that of uracil
itself, so the chance of tautomerization process in the azulene
compound requires less activation energy by comparing the
tautomerization process of uracil. In particular, the presence of one or
more of the variants of the uracil-like DNA in rare forms may increase
the neglecting the original nucleotides of the cell and may cause
mutations. Thus, inhibiting the growth of the cancer cell occurs easier
and faster in the case of azulene compound than in uracil.
•Since proton affinity or deprotonation enthalpy of the functional
groups N-H and C = O can also cause mutations in the DNA by
causing an error in the complementary rules of the double DNA tape
and changing the ability to form hydrogen bonds and thus cancer cell
was killed for incomplete DNA tape. By comparing the obtained
results, in the case of azulene, the greater the ability to acquire the
proton for the functional group C = O and the greater the ability to
remove the proton for the NH group than uracil. Finally, mutation and
killing tumor are occur.
•When comparing the reactivity of uracil and it is analogue (azulene),
we found that The HOMO-LUMO energy gaps of uracil case is larger
than that of azulene respectively this means that in any excitation
process, the AZU1 needed less energy. Lower value in the HOMO
and LUMO energy gap explains the charge transfer interactions taking
place within the molecule (for azulene) easier than that of uracil. And
thus azulene can forming easily covalent bond with pyrimidine
synthetized enzyme causing block for cancer or virus growth.
•Therefore, it is recommended that in the end, due to the importance of
azulene as an alternative to uracil, it is necessary to find ways to
synthesis and study this new compound.