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.