List of Tables � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � �� � � �� �� � � �
�CHAPTER 1
INTRODUCTION
1.1General
Heterocyclic compounds containing nitrogen atom constitute a
prominent class of bioactive molecules including both aromatic and
aliphatic systems such as pyridine, pyrimidine, pyrrolidine, azetidine and
piperidine. Among the saturated heterocycles, piperidine group forms a
large number of derivatives which are having many applications in the
field of medicinal chemistry, agricultural chemistry, material chemistry
and others. In nature itself, piperidine nucleus is present in many
alkaloids widely accepted as drugs. Several substituted piperidine
derivatives have been synthesized by Mannich condensation of
aldehydes, ketone and primary amines/ammonium acetate. Biological
effects of these synthesized molecules also evaluated through in vivo as
well as in vitro assays.
Functionalized piperidines and their derivatives are important
pharmacophores which are present in many pharmaceuticals [1].
Substituted piperidines particularly 2– and/or 2,6–disubstituted
piperidines are synthetically important [2,3] as they exhibit wide
spectrum of biological activities [2e]. Likewise 3,5–disubstituted
piperidines are important fundamentally as backbones for alkaloids, [4a]
high affinity agonists of human GABA–A receptors,[4b] farnesyl–protein
transferase inhibitors [4c] and continue to be basic moieties in
pharmaceutical research and have been target molecules in organic
synthesis [5–7].
4–Piperidone is an important derivative as well as an intermediate
in the manufacture of certain chemicals and pharmaceutical drugs [8]
such as fentanyl, carfentanyl and ramifentanyl. Further, compounds with
4–piperidone nucleus show desirable biological properties viz. antiviral
[9], antitumor [10], central nervous system stimulant [11], analgesic [12],
anticancer [13] and antimicrobial activity [14].
� � � � � � � � � � � � � � ! " # � $ �1.2 Literature review of 3–alkyl and 3,5–dialkyl–2,6–
diarylpiperidin–4–ones
A facile, multicomponent Mannich reaction (Scheme 1) of
aromatic aldehyde, ketone and ammonium acetate or amine as
reported [15] by Noller and Baliah being the simplest procedure
among the several reported methods to synthesize various substituted
4–piperidones till date. Easy separation of products, simplicity and
yield are some of the notable advantages of this method.
13C NMR spectral studies of several 1–hetera–2,6–diaryl–4–
cyclohexanones have been carried out by Ramalingam et al.[16] to
account for the conformational priority of the piperidine ring system in
comparison with similar thia , oxa and N–Me ring systems.
A detailed review about the synthesis of 2,6–disubstituted
piperidines, oxanes and thianes has been reported by Baliah et al.[17]
encompassing various derivatives of 2,6–diarylpiperidin–4–ones. This
review includes several methods developed for the synthesis of
4–piperidones and their N–alkyl and N–aryl derivatives.
% � � � � � � � � � � � � � ! " # � $ �Bhaskar Reddy and others [18] have made a study on the
reactivity of 3–methyl–2,6–diphenyl–4–piperidone. In this study
transformation of 4–piperidones into a variety of heterocyclic
compounds such as diazepinone, oxazepinone, thiadiazole,
γ–carboline, isoxazolyl and pyrazolyl tetrahydro pyridines were
envisaged.
A report [19] about the synthesis, stereochemistry and
antimicrobial activity of 2,6–diaryl–(3–arylthio)piperidin–4–ones as
given in the Scheme 2 reported in the literature. The report narrates
the conformational aspects and structure activity relationship of the
synthesized derivatives.
Manimekalai et al.[20] have made a detailed study about the
protonation effect on chemical shifts of some picrate derivatives of
4–piperidones and the study revealed that the syn diaxial interaction
between the axial N–H bond and axial hydrogen at C5 causes the
difference in the chemical shift of the above highly negative.
Synthesis and spectral studies of some heteroarylpiperidin–4–ones
and their derivatives have been carried out to establish the conformational
preference of them in the liquid state by Manimekalai and others [21]. The
variation of stereochemical features with various substituents at the 3- and
5- positions on the piperidine ring is explained in detail in the report.
& � � � � � � � � � � � � � ! " # � $ �
Antimicrobial evaluation along with the synthesis and
stereochemical studies of 3–benzyl–2,6–diarylpiperidin–4–ones and
their derivatives has been reported in the literature [22]. In this study,
conformational analysis of the synthesized compounds has been
carried out and compared with the theoretically derived structures.
Detailed evaluation of compounds against selected bacterial and
fungal strains has also been carried out.
The environmentally benign one–pot synthesis of 1–methyl–2,6–
diarylpiperidin–4–ones (Scheme 3) using montmorrilonite K–10 as a
catalyst has been developed by Nithya and co–workers [23].
Antimicrobial evaluation of some selected synthesized compounds has
also been done by the same research group.
Stereospecific synthesis of 4–piperidone through double
Mannich reaction and tandem cyclization using I2 as a catalyst has
been reported [24]. The starting materials used are unactivated
ketones and Schiff bases (Scheme 4).
Jia et al. [25] reported the cross double Mannich reaction
(Scheme 5) catalyzed by I2. Stereospecificity and efficiency are some of
the advantages of this protocol.
' � � � � � � � � � � � � � ! " # � $ �
1.3 Literature review of 3–alkyl and 3,5–dialkyl–
2,6diarylpiperidin–4–one oximes and their derivatives
1.3.1 Biological significance of oximes and their derivatives
Oximes and oxime ethers have important pharmaceutical and
synthetic applications such as medicines and pesticides [26]. These
functional groups are incorporated in many medicinally important
molecules used as antibiotics (e.g. gemifloxacin mesylate), drugs used
in the treatment of organophosphate poisoning (e.g. pralidoxime
chloride, obidoxime chloride etc) caused by insecticides such as
malathion and diazinon. Similarly, Fluvoxamine, an antidepressant
drug belonging to the group of selective serotonin reuptake inhibitors
(SSRIs) also contains oxime ether functionality in its structure. Both
O–alkyl and O–aryl oximes have been demonstrated to be stable at
( � � � � � � � � � � � � � ! " # � $ �physiological pH with O–alkyl oxime present in a number of approved
drugs [27].
Besides their use in the medicinal field, oxime–ether derivatives
are also widely used in agriculture as insecticides [28], fungicides [29],
herbicides [30] and in the senescence of cut carnation flowers [31].
1.3.2 Synthetic methods of 4–piperidone oximes and oxime
ethers
NMR spectral studies (1H and 13C) of some piperidin–4–one
oximes have been carried out by Pandiarajan et al [32].
Conformational aspects of the piperidinyl system have been discussed
in the report. Similarly, certain N–hydroxy oximes of piperidin–4–ones
synthesized from dibenzalacetone and structural elucidation of the
same through 1D and 2D NMR spectra has also been carried out by
Aguilera and co–workers [33]. A report about the spectral studies of
some sterically hindered oximes of 2,6–diarylpiperidin–4–ones has
also been available in the literature [34].
Synthesis and biological activities of some oxime derivatives of
2,6–diarylpiperidin–4–ones with and without substituents at N atom
) � � � � � � � � � � � � � ! " # � $ �were studied by Balasubramanian et al. [35] and Ramesh Kumar et al.
[36]. Oximes of 1–acyl–2,6–diarypiperidin–4–ones with i–Pr substituent
at the C3 carbon have been synthesized and their spectral along with
the computational studies have been reported by some researchers
[37,38].
Ramalingan et al. [39] have reported the synthesis of O–benzyl
oxime ethers of 1–methyl–2,6–diarylpiperidin–4–ones for the first time
by following the Scheme 6. Study about the stereochemistry as well
as antimicrobial evaluation of the synthesized oxime ethers is also
elaborated in the report. Similarly, O–benzyl oxime ethers of
N–unsubstituted piperidin–4–one analogues have been synthesized
through Scheme 7 and their NMR spectral studies were carried out
by Parthiban et al. [40].
* � � � � � � � � � � � � � ! " # � $ � Synthesis of polyfunctionalized piperidone oxime ethers and
their cytotoxicity on HeLa cells has been studied by Parthiban et al.
[41]. The synthetic protocol followed is shown in Scheme 8.
Some oximes and benzyl oxime ethers of N–allyl piperidin–4–ones
have been synthesized (Scheme 9) by Narayanan et al.[42] The spectral,
single crystal X–ray diffraction and biological evaluation of the same have
also been done by the same research group to explore the biological
properties.
A recent report [43] about the synthesis and cytotoxicity studies of
N–benzyl piperidin–4–one oximes available in the literature is showing the
growing research on the oxime functionality
+ � � � � � � � � � � � � � ! " # � $ �
, - � � � � � � � � � � � � � ! " # � $ �1.4 Literature review of 3–alkyl and 3,5–dialkyl–2,6–
diarylpiperidin–4–one hydrazones and their derivatives
1.4.1 Industrial and Biological significance of hydrazones
Hydrazones are having remarkable physiological and biological
activities and also found application as insecticides, anticoagulants,
antitumor agents, antioxidants and plant growth regulators.[44–49]
Metal complexes formed from hydrazone ligands are having
application in non–liner optics, sensors, medicine etc.[50] Several
anti–inflammatory, antinociceptive, and antiplatelet active drugs
contain hydrazone and acylhydrazone moieties as core
pharmacophore units in their structure [51].
1.4.2 Biological significance of cyano group
The biocompatibility of the nitrile functionality supports the
prevalence of the nitrile–containing pharmaceuticals and their
continued clinical trials [52]. They are characterized by their short,
polarized triple bond [53]. Only a minimum steric demand
(a cylindrical diameter of 3.6 Å) [54] is required for it when compared
to a methyl group (for which the steric requirement is eight times
higher). Further, nitriles play an important role as hydrogen bond
acceptors [53,55]. Certain recent drugs such as vildagliptin,
anastrazole and saxagliptin are having a cyano group in their
structure indicating its importance.
. . / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 91.4.3 Role of azoles in synthesis and medicinal fields
Azoles are forming a crucial part in the history of heterocyclic
chemistry and also been used as synthons in synthetic organic
chemistry. The growing interest in the research of azole chemistry is
pertaining to the versatility of azole groups in chemotherapeutical
activity. Reports are available about the benzotriazole derivative which
are potent in biological activity [56,57] The role of benzotriazole
derivatives as a precursor in organic syntheses [58],antiprotozoal [59],
antimicrobial [60], anticonvulsant, anti–inflammatory [61] and anti–
tumor [62] agents has been proven by several researchers.
The synthesis of some N–aroyl hydrazones (I) and NMR spectral
studies which revealed the amido–imidol tautomerism has been
reported by Manimeklai et al. [63]. They also carried out the synthesis
and spectral studies of some hydrazones of heteroarylpiperidin–4–ones
(II) [64].
A single crystal X–ray diffraction study of isonictinoyl hydrazone
of 3,3–dimethyl–2,6–diphenylpiperidin–4–one (III)has been undertaken
by Sankar and others [65].
. ? / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9
NMR spectral study of some 2,6–diarylpiperidin–4–one
(3’–hydroxy–2’–naphthoyl)hydrazones with special reference to γ–syn
effect has been done by Sylvestre and Pandiarajan [66]. The
investigated compounds have been synthesized via the Scheme 10
given below.
Xavier and co–workers [67] have made the synthesis (Scheme 11),
NMR spectral studies and antimicrobial evaluation of some
2–(benzothiazol–2–yl)–1–(alkyl–2,6–diarylpiperidin–4–ylidene)hydrazine
derivatives. Application of 2D NMR spectral techniques and SAR
investigation are some of the highlights in that study.
. @ / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9
Recently, the synthesis, antioxidant, antitumor and
antimicrobial activity evaluation of thiadiazole based acid hydrazones
of piperidin–4–ones has been reported by Kodisundaram et al.[68]
Structure activity correlations exhibited by different derivatives are
discussed. Synthetic procedure involved is depicted in Scheme 12.
1.5 Literature review of alkyl thiocyanates and N–acyl
derivatives of 3–alkyl–2,6–diarylpiperidin–4–ones
Thiocyanate group is present in various anticancer natural
products formed by deglycosylation of glucosinolates derived from
cruciferous vegetables [69]. Further, this functional group could be
used as a masked mercapto group and as a precursor for sulphur
. A / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9containing heterocycles. Their role as pesticides [70,71] in agriculture
is also significant industrially. Other important applications of alkyl
thiocyanates are biocidal [72], antiasthmatic [73], vulcanization
accelerators [74] etc.
The synthetic applications of organic thiocyanates are
exemplified by their use in the synthesis of sulphur–containing
compounds such as sulphur heterocycles [75], sulfides [76], cyano–
thiolated compounds [77], and nitriles (through desulphuration) [78].
Despite the above facts, it is pertinent to note that thiocyanate moiety
is present in some biologically active natural products [79].
A study on the reactivity of 3–methyl–2,6–diphenylpiperidin–4–
one has been carried out by Bhaskar Reddy et al.[80]. Bicyclic, spiro
as well as N–acetyl derivatives of the piperidine were synthesized and
characterized through spectral studies and presented in that work.
Krishna Pillay and co–workers [81] have discussed the
conformational analysis of some heterocyclic systems based on
N–aroyl derivatives of piperidin–4–ones (IV). A comparison of the
results of spectral analysis with X–ray crystallographic data has also
been a part of that study.
. B / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9 Crystallographic studies of N–phenyl acetyl and N–diphenyl
acetyl derivatives of piperidin–4–one (V and VI) have been reported
[82]. The conformations and non–covalent interactions were studied
through the X–ray diffraction analysis.
A report by Aridoss et al. [83] about the synthesis (Scheme 13) and
antimicrobial studies of N–chloroacetyl–2,6–diarylpiperidin–4–ones is
available in the literature in which piperidin–4–ones with varying
substituents at C3/C5 carbons and phenyl rings have been
synthesized from corresponding piperidien–4–ones and chloroacetyl
chloride. Marked antibacterial and antifungal potencies are explored
through antimicrobial screening.
The same research group [84] has synthesized some
N–morpholinoacetyl–2,6–diarylpiperidin–4–ones by applying Scheme
14, studied their stereochemistry and evaluated the antimicrobial
activity against selected microorganisms. Significant activity against
C. Albicans, A. Flavus and Rhizopus sp. exhibited by synthesized
compounds has been observed.
. C / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9
Vimalraj and others [85] have reported the synthesis and
structural studies of N–benzoyl derivative of piperidin–4–one oxime.
In that report a comparative study between spectral and
crystallographic analysis have been carried out and possible
conformational preferences of the molecule was inferred.
Some heteroaryl piperidin–4–one oximes with C3–isopropyl
substituent have been synthesized and spectral along with
computational studies carried out by Manimekalai et al.[86] Presence
of two possible rotamers (VII A and VII B) observed from NMR spectra
was also supported by computational studies undertaken by the
researchers.
. D / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9
. E / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9Structural conformation of N–acryloyl derivative of 3–methyl–
2,6–di(p–tolyl)piperidin–4–one has been reported in the literature [87].
Twist boat conformational preference of the molecule in the solid state
was revealed by this study
Design and synthesis of piperazine unit inbuilt derivatives of
piperidin–4–ones and their antitubercular and antimicrobial assay
have been carried out (Scheme 15) by Rani et al. [88]. Various
derivatives synthesized by them have been characterized through
spectral and single crystal X–ray diffraction analysis
1.6 Literature review of coumarin and fused piperidine
derivatives
Coumarins and their derivatives are being attractive to the
research community because of their promising biological, synthetic
and industrial applications. Their uses as insecticides [89], optical
brighteners [90], laser dyes [91], inhibitors of platelet aggregation [92],
anticancer [93], antibacterial [94] and antifungal [95] attracted the
research community to concentrate on them.
Geiparvarin, a naturally occurring compound having coumarin
part in its structure has been reported to be active against a variety of
cell lines including sarcoma 180, Lewis lung carcinoma, P–388
lymphocytic leukemia and Walker 256 carcinosarcoma [96]. Warfarin
and bis–hydroxycoumarins have been therapeutically used as oral
anticoagulants [97], β–adrenergic blocking agents [98] and
vasorelaxants [99].
. F / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9
Structures having piperidine and pyran rings fused together have
been synthesized (Scheme 16) from chalcones derived from 1–methyl
piperidin–4–one and shown to be antimycobacterial by Ranjith Kumar
and others [100,101a].
? G / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 91.7 NMR spectroscopy
1H and 13C NMR spectroscopy are the widely used tools in the
structural elucidation of organic compounds. The 1H and
13C chemical shifts are affected by the electron density around the
nuclei concerned and tell about the environment of the protons and
the carbons.
1.7.1 1H NMR spectroscopy and its significance
Diamagnetic anisotropy arises due to the presence of ring
currents, caused in most cases by π electrons and affects the
chemical shifts. This can either shield or deshield a proton.
–C bonds are small compared
to that of the circulating π electrons. Due to this effect, the equatorial
protons in cyclohexane and similar six membered rings are deshielded
by about 0.5 ppm than the corresponding axial protons.
The stereochemistry of a compound can be assigned from the
1H NMR chemical shifts, since steric, polar and conformational effects
alter the proton chemical shifts. The influence of the substituents on
the chemical shift of the ring protons can be used for configurational
assignments. Coupling constants are of immense use in
configurational and conformational studies since vicinal coupling
constants between two protons depend on their relative positions.
In saturated systems, the vicinal coupling constant depends on the
dihedral angle between the coupled protons.
It has been found by Karplus [101b] that using valence bond
calculations, the vicinal coupling constant between two protons will
have a maximum value for any system when the torsional angle
between them is 180°. Karplus also pointed out that the vicinal
coupling constants decrease with increase in the electronegativities of
the substituents in the C–C segment.
? . / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 91.7.2 13C NMR spectroscopy and its significance
The 13C chemical shifts of six–membered ring compounds are
also influenced by many factors such as the inductive effect of the
substituents, hybridization state of the observed nucleus, van der
Waals and steric effects between closely spaced nuclei, electric fields
originating from molecular dipoles or point charges, hyper
conjugation, mesomeric interactions in π electron systems,
diamagnetic shielding due to heavy substituents and neighbouring
anisotropic effects. Further, the electrostatic effects owing to the presence
of a heteroatom in the cyclohexane moiety and steric perturbation effects
are of intrinsic importance in this context.
The effect of a heteroatom present in a six membered cyclic system
has been studied any The deshielding effect of heteroatom on the benzylic
carbon of 1–hetera–2,6–diaryl–4–cyclohexanones has been found in the
order as O>N–Me>NH>S. The heteroatom causes an upfield resonance of
the carbonyl group attributed as a field effect. 13C NMR spectra is of
importance in deciding the configuration of carbonyl derivatives such as
oximes, hydrazones, thiosemicarbazones and semicarbazones that the
distinction between E and Z isomers could be done from the knowledge of
the 13C chemical shift values of the carbon atoms present either sides of
the imino group.
1.7.3 2D–NMR spectral techniques
1.7.3.1 1H–1H COSY (Homonuclear Correlation Spectroscopy)
This technique is also known as HOMOCOSY and reveals the
correlation between the coupled protons as cross peaks in the spectrum.
In this type of spectra off–diagonal peaks are considered significant and
they are exhibited by protons that are having measurable coupling.
The diagonal peaks present in the spectrum are due to the chemical shift
equivalent protons are they are deemed to be unimportant in deriving
information.
? ? / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 91.7.3.2 1H–13C COSY (Heteronuclear Single Quantum Coherence–
HSQC)
This two dimensional NMR technique correlates 13C nuclei with
directly attached protons. Only one bond coupling between a carbon and
its attached proton is detected eliminating two and three bond coupling
in this experiment. It is of importance in structural elucidation of organic
compounds.
1.7.3.3 DEPT (Distortion less Enhancement by Polarization
Transfer)
It is a two dimensional NMR spectral technique [101b] in which
three different variants are available such DEPT–45, DEPT–90 and
DEPT–135 of which DEPT–135 is the widely used one. In this type of
spectrum the carbon having odd number of protons (CH and CH3)
exhibit positive peaks and carbons with even number protons (CH2)
are observed in the negative part of the spectrum while quaternary
carbons don’t show their peaks. This technique finds its use in the
case of large molecules with many types of carbon atoms.
1.7.3.4 HMBC (Heteronuclear Multiple Bond Coherence)
This is also a two dimensional technique which detects the long
range coupling between carbons and protons avoiding one bond
coupling. It is useful in the case of assigning carbon signals of
compounds having more quaternary carbon atoms.
1.7.3.5 NOESY (Nuclear Overhauser Exchange Spectroscopy)
The Nuclear Overhauser Enhancement (NOE) can be used to
demonstrate that two protons or group of protons are in close
proximity within the molecule and is therefore of considerable value in
the study of molecular geometry. In this type of spectrum, cross peaks
reveal the spatial proximity of the protons. The usual range of protons
detected in this spectrum is 2–5 Å.
? @ / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 91.8 Single crystal X–ray diffraction technique
X–ray crystallography is the chief method for characterizing the
atomic structure of solid materials. It is a method of determining the
arrangement of atoms within a crystal and it involves X–rays to get a
diffraction pattern generated by the scattering of the same by
electrons present in the crystal lattices. A three dimensional picture of
the density of the electrons within the crystal can be produced from
the angles, bond distances and dihedral angles.
During the process of X–ray diffraction, the intensities of
various diffracted beams are collected by passing the X–ray beam
through the crystal and this process is called (intensity) data
collection. Then this data is converted into a more corrected and
usable form by preliminary manipulation which is known as data
reduction. After the data reduction step, a process known as
refinement by which electron densities map that is closer to the real
structure is obtained. Structure refinement is the process of
improving the parameters for all atoms in an approximate (trial)
structure, until the best fit of calculated structure factor amplitudes
to those observed is obtained.
The atomic positions in the molecular structure are determined
by noting the electron density maxima in the unit cell and it is
dependent on volume of the unit cell and structure factor.
The structure factor is the resultant of all waves scattered in the
direction of the reflections by all the atoms in the unit cell. The close
agreement between observed structure factors and calculated
structure factors represents the true structure. It is represented by a
residual index called R–factor, which describes the correctness of the
model structure. R=0 indicates a perfect structure and any value of
R<0.5 indicates a close correspondence between the trial and real
structure.
? A / 0 1 2 3 4 5 6 7 8 9 3 5 : ; < = 3 > : 9Now–a–days structure solution and structure refinement is
carried out using SHELX 97 program package developed by
Prof. George Sheldrick of University of Gottingen, Germany. It is a set
of programs for crystal structure determination from single crystal
diffraction data.
1.9 Antimicrobial assay methods
Antimicrobial susceptibility tests measures the ability of an
antimicrobial agent to inhibit the bacterial and fungal growth in–vitro.
In general, methods used are classified into two namely:
· Disc diffusion method
· Serial dilution method
Disc diffusion method or Kirby–Bauer method is recommended
as a general purpose method or a qualitative method in which
inhibitory power of the antimicrobial agent is arbitrarily assigned
based on their zone of inhibition (ZI) values observed while serial
dilution method is used to determine minimum inhibitory
concentration (MIC) of the antimicrobial agent.
A preliminary investigation of a group of biologically active
molecules could be proceeded through disc diffusion method and from
the results obtained a further step to find the suitability of the
antimicrobial agent towards particular microorganism be tested via
serial dilution method. Therefore we can arrive at a conclusion about
the biological efficacy of the compounds in a qualitative and
quantitative basis.
1.10 Theoretical studies of molecular systems
Theoretical chemistry seeks to provide explanations to physical
and chemical observations. It includes fundamental laws of physics
such as Coulomb's law, the Virial theorem, Planck's law, Pauli's
H I J K L M N O P Q R S T N P U V W X N Y U Texclusion principle and many others to explain and predict observed
phenomena. A theoretical model or method is a way to model a system
using a specific set of approximations. The approximations are then
combined with a calculation algorithm and applied to atomic orbitals,
defined by the basis set.
A basis set is a set of wave functions that describes the shape of
atomic orbitals which are later combined linearly by LCAO method to
form molecular orbitals. The level of approximation is directly related
to the basis set used. In general, the theoretical methods [101c] can
be divided into four main types:
· Semi empirical
· Ab initio
· Density Functional and
· Molecular Mechanics
The selection of a theoretical method depends on the size of the
system and on the level of approximation.
Ab initio methods of computation are based only on theoretical
principles and not on the experimental data. These include Z Hartree–Fock model (HF) Z Moller–Plesset (MPn) and Z Configuration Interaction (CI).
HF model uses the approximation that Coulombic electron–
electron repulsion can be averaged, instead of considering explicit
repulsion interactions. Further, this method can be splitted into two
namely: UHF (unrestricted) and RHF (restricted).
CI calculations are most often used for excited states.
H [ J K L M N O P Q R S T N P U V W X N Y U TSemi empirical methods use certain number of experimental
data through the calculation and usually applied for very big systems,
since they can handle large amounts of calculation. Some examples of
semi empirical methods are ZINDO (used for computing
UV transitions) and AM1 (Austin Model–1, used to model organic
molecules)
Density Functional Theory (DFT) methods differ from
HF methods in such a way that it uses electron density instead of a
wave function to compute the energy of the system. Some examples of
these methods are B3LYP (Beckman Lee Young Par hybrid functional)
correlation method, PW91 (gradient corrected) and VWN (local density
approximated).
Molecular Mechanics (MM) approximate atoms as spheres and
bonds as springs and uses an algebraic equation for the energy
calculation, not a wave function or electron density. UFF (Universal
Force Field) and MMFF (Merck Molecular Force Field) are examples of
MM methods.
1.11 Scope of the present investigation
From the available literature reports about the significance of
piperidine derivatives, oximes, hydrazones, azoles, alkyl thiocyanates
and coumarin derivatives, we have planned and carried out the
synthesis of a library of compounds having active functional groups as
pharmacophores. It is also known from the literature that the
stereochemistry of the biologically active molecules plays a pivotal role
in deciding the biological activities. Among the characterization
techniques, NMR spectroscopy is an effective tool to study about the
conformation and relative stereochemistry of cyclic system with
relatively rigid structures. Similarly single crystal X–ray diffraction
analysis is considered as an ultimate technique or structural
investigation. Therefore in the present work, synthesis, NMR spectral
H \ J K L M N O P Q R S T N P U V W X N Y U Tcharacterization along with IR and mass spectral studies are
undertaken for some piperidine derivatives with varied functionalities.
Structural studies with the aid of 1–D and 2–D NMR spectroscopy are
the main task of the present work. Antimicrobial assay, single crystal
X–ray analysis and theoretical studies (based on HF Theory) are also
done for some selected compounds. Stereochemical investigation is
limited to find relative stereochemistry and determination of absolute
stereochemistry is beyond the scope of the present work.