Chapter-1 SEMICARBAZONE AND THIOSEMICARBAZONE A BRIEF INTRODUCTION------------------------------------------1-30 1.1 Introduction--------------------------------------------------------------1-4 1.2 Semicarbazone and thiosemicarbazone in the biological filed
A survey-------------------------------------------------------------------4-81.3 Stereochemistry, bonding and nature of coordination of
Semicarbazone and thiosemicarbazones----------------------------8-16 1.4 Objective and scope of present work--------------------------------16-171.5 Introduction to the relevant analytical techniques---------------18-23 1.6 Conclusion-------------------------------------------------------------------241.7 References----------------------------------------------------------------25-30
1
CHAPTER-1
SEMICARBAZONE AND THIOSEMICARBAZONE A BRIEF INTRODUCTION
1.1 INTRODUCTION
Coordination compounds have been a challenge to the inorganic chemist since
they were identified in the nineteenth century. After the profound studies done
by Alfred Werner, inorganic chemistry witnessed a great outflow of
coordination compounds, with unique structural characteristics and diverse
applications. The stereochemistry of coordination compounds is one of major
interests of the coordination chemist. The development of instrumental
techniques provides methods of investigating thermal, spectral and magnetic
properties of metal complexes. Coordination compounds can have a wide
variety of structures depending on the metal ion, coordination number and
denticity of the ligands used. The presence of more electronegative nitrogen,
oxygen or sulfur atoms on the ligand structure is established to enhance the
coordination possibilities of ligands.
Thiosemicarbazone are very versatile ligands. They can coordinate to
metal as neutral molecules or after deprotonation as anionic ligands and can
Chapter 1
2
adopt a variety of different coordination modes. Thiosemicarbazones and
semicarbazones act as ligands because;
1. They have better co-ordination tendency.
2. They form more stable complexes.
3. They have better selectivity.
4. They may form macrocyclic ligands
5. They have the ability to produce some new and unique complexes
with enhanced biological and analytical properties1. Certain
thiosemicarbazones are relatively specific inhibitors of ribonucleotide
reductase, which is an important metabolic target for the development
of chemotherapeutic agents against cancer2 .
Thiosemicarbazone usually act as chelating ligands with transition metal ion
bonding through the sulphur and hydrazine nitrogen atom. Thiosemicarbazone
and their complexes have received considerable attention because of their
pharmacological activities.
Semicarbazone are the schiff bases, usually obtained by condensation of
semicarbazide with suitable aldehydes and ketones Fig(1.1).
R1
R2
+ NH
O
NHH N 22
H+
H2O-
R1
R2
O N
NH
NH2
O
Fig.1.1: Method of synthesis of Semicarbazone
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
3
An interesting artibute of semicarbazone is that in solid state, they
predominately exist in the keto form, whereas in solution state, they exhibit a
keto-enol tautomerism. Keto form act as neutral bidentate ligand and the enol
form can deprotonate and serve as mono –anionic bidentate ligand in metal
complexes. Thus semicarbazone are versatile ligands in both neutral and anionic
forms fig (1.2) keto-enol tautomerism of semicarbazones.
Both tautomeric forms have an efficient electron delocalization along the
semicarbazone moiety. Aromatic substituent on semicarbazone skeleton can
furher enhance the delocalization of electron charge density. These classes of
compounds usually react with metallic cations giving complexes in which the
semicarbazone behave as chelating ligands upon coordination to a metal centre,
the delocalization is further increased through the metal chelate rings. The
coordination possibilities are further increased if the substituent has additional
donor atoms.
Chapter 1
4
The semicarbazone and thiosemicarbazone usually behave as chelating
ligands and usually react with metallic cations giving complexes.They are
versatile ligands in both neutral and anionic forms. Metal complexes of
semicarbazone and thio-semicarbazone have gained special attention due to
their importance in medicine and biological system3.taaaa
1.2 SEMICARBAZONE AND THIOSEMICARBAZONE IN THE
BIOLOGICAL FILED A SURVEY
Semicarbazones present a wide range of bioactivities, and their chemistry and
pharmacological applications have been extensively investigated. The biological
properties of semicarbazones are often related to metal ion coordination. Firstly,
lipophilicity, which controls the rate of entry into the cell, is modified by
coordination4. Also, the metal complex can be more active than the free ligand.
The mechanism of action can involve binding to a metal in vivo or the metal
complex may be a vehicle for activation of the ligand as the cytotoxic agent.
Moreover, coordination may lead to significant reduction of drug-resistance5.
The semicarbazone and thiosemicarbazone usually behave as chelating ligands
and usually react with metallic cations giving complexes. Copper (II)
complexes with semicarbazides and thiosemicarbazides have received much
attention due to their wide range of applications with as an antibacterial6-9,
antifungal10-13, In addition, they also have been used in the treatment of a
number of tumors, including Hodgkin,s disease.
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
5
In addition thio- and semicarbazone possess a wide range of bioactivities
and their chemistry and pharmacological applications have been extensively
investigated the more significant bioactivities of a variety of semicarbazone
(antiprotozoa and anticonvulsant) and thiosemicarbazone (antibacterial,
antifungal, antitumoral, antiviral) and their metal complexes have been
reviewed together with the proposed mechanism of action and structure
reactivity relationship14-15.
A variety of 5-nitrofuryl semicarbazone derivatives have been developed
for the therapy of Chagas disease, a major problem in the Central and the South
America16. 4-Bromo benzaldehyde semicarbazone has been used as
anticonvulsant. Recently, a review reported on the anticonvulsant activity of
thiosemicarbazones, semicarbazones and hydrazones derived from aromatic and
unsaturated carbonyl compounds as well as from other precursors17. In contrast
to thiosemicarbazones, literature records fewer examples of semicarbazones
presenting significant anticancer and cytotoxic activity but some nitroso,
naphtopyran, and fluorine derivatives showed anti-leukemia effect in mice18.
Coordination chemistry of PLSC- based complex (pyridoxal-
semicarbazone) proved to be very interesting as this ligands can exist in
neutral, mono and dianionic form depending on PH , while in most predominant
tridentate coordination mode achieved through hydragenic nitrogen , phenolic
and carbonyl oxygen atom, allows it to be an excellent chelating ligand19.
Chapter 1
6
The ligands based on semicarbazone and pyridoxal moieties (forms found
in vitamin B6) has an enormous potential as a biologically active reagents as it
has been demonstrated that transition metal complexes incorporating
semicarbazone show biological activity, in particular, with regard to biological
importance, nickel (II) complex with semicarbazone ligands show antibacterial
activity20 and copper(II) complexes containing semicarbazones have also
displayed biological properties21-23.Additionally, several nickel (II) complexes
with octadiensemicarbazone exhibit strong inhibitory activity against
staphylococcus aureus and E. coli24. In vitro anticancer studied of several
nickel(II) complexes with napthoqinone semicarbazone and thiosemicarbazone
on MCF-7 human breast cancer cells reveal that semicarbazone derivative with
nickel(II) complexes is more actively inhibiting cell proliferation than
thiosemicarbazone 25.
A number of authors have been interested in investigating the biological
and medicinal properties of transition metal complexes of semicarbazones and
thiosemicarbazones in recent years. New square planer complexes of general
formula [M(NNS)Cl] [M=Pd(II), Pt(II), NNS=anionic forms of 6 methyl-2-
formyl pyridine Schiff bases of S-benzyl dithiocarbazates have been prepared.
Both Schiff bases exhibit strong cytotoxicity against the human ovarium cancer
(Caov-3) cell lines, the S-methyl derivative being two times more active than
the S-benzyl derivative26. Palladium(II) and platinum (II) complexes
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
7
carbothioamide have been prepared and screened for their antimicrobial activity
against the fungi Macrophomina phaseolina and fusarium oxysporium by agar
plate technique.The results prove that the compounds exhibit and it is important
to note that the metal chelates show more inhibitory effects than the parent
ligands. The increased lipophilic character of these complexes seems to be
responsible for their enhanced biological potency27.Novel metal benzoic
semicarbazone complexes have been synthesized from substituted
benzoisemicarbazones. These compounds for their antimicrobial activities
against four test organism E.coli, S.aureus, Ps. aeruginosa, B. subtilis at a
against their organism were determined by serial dilution method28. A good
deal of work has been reported on the preparation and structural investigation of
semicarbazone and their complexes29-30.
The square planar platinum(II) and palladium (II) complexes M(HL)Cl2
and M(L)Cl type with thiosemicarbazone ligands derived from
phenylacetaldehyde and 2-formylpyridine showed high cytotoxicity in vitro
against HL60 Leukemia and P388 mouse leukemia cell lines31. While
platinum(II) and palladium (II) binuclear complexes with p-isopropyl
benzaldehyde thiosemicarbazone ligands exhibit strong cytotoxic activities on
mouse tumor cell inhibition32-33.
Chapter 1
8
Schiff bases are regarded as “privileged ligands” due to their capability to form
complexes with a wide range of transition metal ions yielding stable and
intensely colored metal complexes. Some of them have been shown to exhibit
interesting physical and chemical properties and potential biological34-39
activities. Metal complexes of Ni(II) are found to as a sensor40 and also
nanoparticle act as a sensor41. Semicarbazone are frequently used in the
qualitative organic analysis of carbonyl compounds42.
1.3 Stereochemistry, bonding and nature of coordination of semicarbazones
A review of semicarbazone and thiosemicarbazone43 showed that in free
unsubstituted semicarbazones in the solid state, the C=N-NH-CO-NH2 backbone
is usually planar, with O atom trans to azomethine N atom.(Fig.1.3)
Fig. 1.3 Structure of semicarbazone
Few semicarbazone are exception to this rule. Although there are several
electronic and steric factors that may contribute to the adoption of this
rearrangement, the most is probably that the trans arrangement places the amine
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
9
and azomethine nitrogen atoms in relative position suitable for
intramolecular hydrogen bonding44.
Interestingly, semicarbazone show a variety of coordination modes with
transition metals, the coordination mode is influenced by the number and type
of substituent. This is because the active donor sites of ligand vary depending
upon the substituent. According to the reports the coordination mode of
semicarbazone is very sensitive towards minor variation in the experimental
conditions. The nature of substituent on the carbonyl compound and metal
salts45.
In most of the complexes we synthesized semicarbazone act as tridentate
ligand and in some cases semicarbazone exhibit as potential quadridentate when
the second pyridyl nitrogen involved in coordination process. The coordination
mode of N4- substituted46 fig.(1.4) is given below.
Fig. 1.4 Coordination mode ONO - tricoordination
Chapter 1
10
The different coordination modes of substituted benzaldehyde semicarbazone
given below47 fig(1.5);
Fig. 1.5 (a)
Fig.1.5 (b)
Fig. 1.5 (c)
Fig. 1.5 (a,b,c) Different Coordination Modes
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
11
Owing the availability of NH-C=S group, thiosemicarbazone exhibit thione –
thiol tautomerism. In solid they exist in thione form but in solution they exist as
an equilibrium mixture of thione and thiol form as shown in the fig.1.6.
Fig. 1.6 Equillibrium mixture of thione and thiol
Presence of N=C, made them to exist as E and Z stereo isomers. Considering
the thermodynamic, E isomer will predominate in the mixture48.The existence
of two forms of E isomer viz EI and EII is reported the EI isomer has more
intermolecular hydrogen bonding49 than EII. The isomer are represented in the
fig.1.7
Chapter 1
12
Fig.1.7 Structure of E and Z stereoisomer, E1 and E11 isomer
The E and Z isomer of 2- formylpyridine thiosemicarbazone as well as those of
the other hetro cyclic thiosemicarbazone has been separated and characterized50.
The stable difference in stereochemistry between isomer was based upon the
degree of shielding obserbed for the 2N proton of the z isomer.
However in most complexes thiosemicarbazone coordinate as bidentate
ligand via the azomethine nitrogen and thione thiol sulphur. When additional
coordination functionality is present. The proximity of the donating centre, the
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
13
ligand will coordinate in a tridentate manner. This can be accomplished
by the neutral molecule or the monobasic anion upon loss of hydrogen.
Besides the denticity variation, consideration of the charge distribution is
complicated in the semicarbazone due to the existence of thione thiol tautomers.
Although the thione form predominates in the solid state, solution of
thiosemicarbazone molecules show a mixture of both tautomers. As a result
depending upon the preparative condition, the metal complexes can be cationic,
neutral or anionic. Most of the earlier investigation of metal thiosemicarbazone
complexes have involved ligands in the uncharged thione form, but a number of
recent reports have featured complexes in which the 2N- hydrogen is lost, and
thiosemicarbazone coordinate in the thiol form51. Furthermore, it is possible to
isolate complexes containing both the neutral and anionic forms of the ligand
bonded to the same metal ion. Ablov and gerbeleu suggested that formation of
these mixed “tautomer” complexes is promoted by trivalent central metal ion
like Cr(III), Fe(III) and Co(III).
Recently we have reported the crystal structure of pyridine 2-
carbaldehyde 4N Phenethyl thiosemicarbazone in which the thiosemicarbazone
group adopts an EE configuration, i.e., trans configuration are obserbed about
both the azomethine and hydrazinic bonds52. Although there are several
electronic and steric factors that may contribute to the adoption of this
arrangement, the most important is probably that the trans arrangement places
Chapter 1
14
the amine and azomethine nitrogen atoms in relative position are
suitable for intramolecular hydrogen bonding53. In fact, the complete
substitution of amine hydrogen result in crystallization with S atom cis with
azomethine nitrogen giving z configuration fig(1.8).
Presence of NH-C=S group in thiosemicarbazone can bring about thione- thiol
tautomerism. In solution thiosemicarbazonees exist as an equilibrium mixture of
thione(III) and thiol (I ) forms fig(1.9).
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
15
Enolization into the thiol form results in an effective conjugation along the
thiosemicarbazone skeleton thus enhancing electron delocalization along the
moiety. In the case of heteroaromatic thiosemicarbazone, delocalization of
electron cloud is extended along with the generation of new potential sites for
coordination to a metal centre, the delocalization is further increased through
the metal chelate rings. This is one of the reason for choosing pyridine-2-
carbaldehyde as the carbonyl base of our ligands. Through thiosemicarbazone
can coordinate to metals in the neutral thione form, usually chelation takes place
through the anion formed by deprotonation of hydrazinic NH groups, via
enolization to the thiol form. The stereochemistry adopted by the
thiosemicarbazone ligand with transition metal ion depends essentially on the
Chapter 1
16
presence of additional coordination sites in the ligand moiety and the charge on
the ligand which in turn is influenced by thione - thiole equilibrium, and pH of
the medium used for reaction. Studies have revealed that steric effects of the
various substituent in the thiosemicarbazone moiety considerably affect the
stereochemistry54.
Thiosemicarbazone can adopt a variety of different coordination modes.
In most of the series, thiosemicarbazone coordinate as bidentate ligands via
azomethine nitrogen and thione/thiolato sulphur. When additional coordination
functionality is present in the proximity of donating centres, the ligands will
coordinate in a tridentate manner. This can be accomplished either by neutral
molecule or by the monobasic anion upon loss of hydrogen. Although the thione
form predominates in the solid state, solution of thiosemicarbazone molecule
show a mixture of both tautomers. As a result, depending upon the preparative
conditions, the metal complexes can be cationic, neutral or anionic.
1.4 Objective and Scope of the present work
The significance of semicarbazone and thiosemicarbazone and their metal
complexes, apart from their diverse chemical and structural characteristics,
stems from not only their potential but also their proved application as
biologically active molecules. The wide application and structural diversity of
metal complexes of semicarbazone prompted us to synthesize the tridentate
NNO- donor semicarbazones and their metal complexes. Due to good chelating
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
17
ability, the present work is mainly concerned with the studies on
complexes of salicylaldehyde, m-hydroxy benzaldehyde and p- hydroxy
benzaldehyde semicarbazones and thiosemicarbazones. By emphasizing this
point the objectives of the present work are as follows:
The Salicylaldehyde semicarbazone/thiosemicarbazone (L1/L2=SSC/
STSC) m-hydroxy benzaldehyde semicarbazone/thiosemicarbazone (L3/L4=m-
HBSC/m-HBTSC), p- hydroxy benzaldehyde semicarbazone\
thiosemicarbazone (L5,L6= p-HBSC/p-HBTSC). The composition of ligand
were determined by the CHN analysis. For the characterization of these
compounds by 1HNMR and IR spectral studies. The metal complexes of Ni2+,
Cu2+, Mn2+ and Co2+ were characterized by 1HNMR, IR and UV spectral
studies. These complexes were characterized various spectroscopic techniques,
magnetic and conductivity studies.This thesis is divided into six chapters. All
the ligands of semicarbazone and thiosemicarbazone, L1, L2, L3, L4, L5, L6 and
the Complexes of [Mn(L4)2Cl2, [Mn(L6)2Cl2], [Ni(L4)2)Cl2], [Ni(L6)2)Cl2],
[Co(L2)2Cl2], [Co(L4)2Br2], [Cu(L2)2Br2] [Cu(L4)2Br2] [Ni(L3)2Br2] have been
screened against Bacteria (a) gram positive Staphylococcus aureus(S aureus),
(b) gram negative Ecoli and fungi Aspergillus niger and Candida albicans by
agar disc diffusion method at conc.-
Chapter 1
18
1.5 Introduction to the relevant analytical techniques
Several methods, conventional and modern are available for elucidating the
structure of ligands and their coordination compounds. The complexes are
characterized by elemental analysis, molar conductance, magnetic susceptibility
measurement and spectral (electronic, IR, EPR, 1HNMR). Studies some of the
physical chemical methods adopted during the present investigation are
discussed below.
1.5.1 Elemental analysis
The C,H and N were analyzed on Carlo-Erba 1106 elemental analyzer. The
nitrogen content of the complexes was determined using kjeldahl, method at
Indian Institute of Technolgy.
1.5.2 Magnetic Susceptibility measurement
The magnetic susceptibility and the magnetic moment are often used to describe
the magnetic behaviour of substance. A magnetic dipole is a macroscopic or
microscopic magnetic system in which the north and south poles are separated
by a short but definte distance. In the presence of a magnetic field, magnetic
dipoles within a material experience a turning effect and become partially
oriented. The magnetic moment refers to the turning effect produced when a
magnetic is placed in a magnetic field. The fundamental unit of magnetic
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
19
moment is the bohr magneton. For isotropic the magnetic susceptibility ( ) is
defined by,
= M/H
Where M is the magnetic moment per unit volume (magnetization) and H
is the strength of magnetic field. The molar susceptibility M is simply defined
as the susceptibility per gram mole .Hence,
M = × molecular weight
The magnetic susceptibility value calculated from magnetic measurement
is the sum of paramagnetic and diamagnetic susceptibility. To calculate the
exact eff), the value of diamagnetic susceptibility
is substracted from the susceptibility calculated from observed results. When
the structural formula of the complexes is correctly known, diamagnetic
correction can be calculated from pascal,s constant.
The magnetic susceptibility measurement were carried out in the
polycrystalline state on a vibrating sample magnetometer (VSM) at 5.0 khz field
strength at room temperature at Indian institute of Technology, Roorkee.
1.5.3 Infrared spectroscopy
The vibrational states of a molecule can be probed in a variety of ways . The
most direct way is infra-red spectroscopy because of vibrational transition
Chapter 1
20
typically require an amount of energy that corresponds to infrared region of the
spectrum 4000 and 400 cm-1 (wavenumber). Radiation in this region can be
utilized in structure determination in coordination chemistry by making use of
the fact that interatomic bonds in ligand absorb it.
Infrared spectra (KBr) were recorded on FTIR spectrum BX-11
spectrophotometer at Sophisticated Instrumentation Facility, Indian Institute of
Technology (IIT), Delhi.
1.5.4 Electronic spectroscopic
Electronic spectroscopy is the measurement of the wavelength and intensity of
absorption of near ultra violet and visible light by a sample. UV- vis
spectroscopy is usually applied to organic molecule and inorganic ions or
complexes. The absorption of UV or visible radiation corresponds to the
excitation of outer electrons.
There are three types of electronic transition that can be considered for
coordination compounds. Possible transitions of , and n electrons are
shown in fig 1.4. Most absorption spectroscopy of ligands is based on n
and transition. Many inorganic species show ligand to metal. Charge
transfer (LMCT) transition and metal to ligand charge transfer (MLCT)
transition(not as common as (LMCT). Transition probability in ligand field
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
21
transition (d-d transition) is determined by the spin selection rule and the
orbital (Laporte) selection rule.
Electronic spectra were recorded on a carry 5ooo, version 1.09 UV- Vis-
NIR Spectrophotometer from solution of compounds in chloroform/DMF at
Inderprastha Engineering Institute, Sahibabad.
1.5.5 NMR Spectroscopy
1H NMR spectra were recorded using Bruker AMX 400 FT-NMR spectrometer
using TMS as the internal standard at Sophisticated Instrumentation Facility,
Indian Institute Technology (IIT), Delhi.
1.5.6 EPR Spectroscopy
Electron paramagnetic resonance is based upon the spllitting of magnetic energy
levels produced by the action of a magnetic field on an unpaired electron
contained in an ion, a molecule or complexes. The free electron behave as a
spinning negatively charged particle with a resulting magnetic moment. By
virtue of its charge and spin an electron act as a bar magnet and can interact
with an external magnetic field. The magnetism of an electron can be expressed
by saying tha
The magnetic moment of an electron is nearly 1000 times greater than
that of a proton and is given by
- g s
Chapter 1
22
Where g is called the spectroscopic splitting factor or gyromagnetic ratio when
electrons are placed in a magnetic field, they will have their energy changed by
a certain number of ergs, given by
= ±
Where H is the strength of magnetic field.
EPR measurement require that an odd or unpaired electron occurs in the
substance. The effect of magnetic moments of nuclei on ESR spectrum is
known as hyperfine interactions and responsible for splitting of ESR line, giving
rise to hyperfine structure. Energy states separated by hyperfine coupling
constant A.
Number of hyperfine lines is given by (2NI+1) .Where n is the number of
equivalent nuclei with spin I. further splitting of states by nearby nuclei, such as
14N is reffered to as superfine coupling . Symmetry can also have an effect on
EPR spectra. If the spectra are obtained from frozen solution from a powder,
Where anisotropy is not averaged from by motion of the molecule, a complex
pattern can emerge, when gx= gy=gz in a perfectly cubic crystal, such a g value
is the isotropic one. In axial environment the g factor are anisotropic (gz = gll
and gx, gy = g ). For a rhombic molecular environment, three g factors are
observed.
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
23
1.5.7 Conductivity measurement
The molar conductivities of the complexes in dimethyl formamide (DMF)
solution (10-3 M) at room temperature were measured using a direct reading on
the ELICO (CM82T) conductivity bridge.
Chapter 1
24
1.6 Conclusion
This chapter has dealt with an extensive literature study relating semicarbazone
and thiosemicarbazone and their transition metal complex. Many authors have
reported anticancer, antibacterial, antifungal, antimalarial, antiviral, antifilarial
and anti –HIV activities of these compounds. They have been against small pox,
leprosy, psoriasis, rheumatism, trypanosomiasis and coccidiosis. The transition
metal complexes are far more biologically active than uncoordinated
semicarbazone and thiosemicarbazone and their enhanced biological activity
has been an active area of investigation among medicinal researchers.
Thiosemicarbazone exist as E and Z isomer and they exhibit thione- thiol
tautomerism.The present work is mainly concerned with the studies on
complexes of salicylaldehyde, m-hydroxy benzaldehyde and p- hydroxy
benzaldehyde semicarbazones and thiosemicarbazones. The composition of
ligand were determined by the CHN analysis. For the characterization of these
compounds by 1HNMR and IR spectral studies. The metal complexes of Ni2+,
Cu2+, Mn2+ and Co2+ were characterized by 1HNMR, IR and UV spectral
studies. These compounds have been screened against Bacteria (a) gram
positive Staphylococcus aureus(S aureus), (b) gram negative Ecoli and fungi
Aspergillus niger and Candida albicans by agar disc diffusion method at conc.-
Semicarbazone and Thiosemicarbazone- A Brief Iintroduction
25
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Chapter 1
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27
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