chapter 2 imidazothiadiazoles -...

Chapter 2 Imidazothiadiazoles

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1.

2-(4-Fluorobenzyl)phenylimidazo[2,1-b][1,3,4]thiadiazole

2.

2-(4-Fluorobenzyl)-6-(4-methoxyphenyl)-5-

morpholin-1-ylmethylimidazo[2,1-b]

[1,3,4]thiadiazole

3.

2-(4-fluoro-benzyl)-6-phenyl- imidazo[2,1-

b][1,3,4]thiadiazole-5-carbaldehyde

4.


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2-(4-Fluorobenzyl)-6-(4-methoxyphenyl)Imidazo[2,1

-b][1,3,4]thiadiazole

5.

2-(Fluorobenzyl)-6-(4-nitrophenyl) imidazo [2,1-

b][1,3,4]thiadiazole

6.

6-(4-Chlorophenyl)-2-(4-fluorobenzyl)

imidazo[2,1-b][1,3,4]thiadiazole

7.

6-(4-Bromophenyl)-2-(4-fluorobenzyl)imidazo[2,1-

b][1,3,4]thiadiazole


53

2 Crystal and molecular structure of Imidazo Thiadiazole derivatives

Section A: Discussion on Imidazothiadiazole derivatives.

For the development of a clinically useful drug, years of cumulative research

have been resulted in providing either a cure for a particular disease or symptomatic

relief from a physiological disorder. A desired pharmacological active compound may

have associated with characteristics that limit its bioavailability, undesirable side

effects, or structural features which adversely influence its metabolism and excretion

from the body. Bioisosterism represents one approach used by the medicinal chemist

for the rational modification of lead compounds into safer and more clinically

effective agents. The concept of bioisosterism is often considered to be qualitative and

intuitive [1]. A bioisostere is a compound resulting from the exchange of an atom or

of a group of atoms with another, broadly similar, atom or group of atoms. The

bioisosteric replacement may be physicochemically or topologically based. The

objective of a bioisosteric replacement is to create a new compound with similar

biological properties to the parent compound.

The topic of bioisosterism has been well reviewed in previous years [2-5]. The

ability of a group of bioisosteres to exhibit similar biological activity has been

attributed to two reasons. One of them is the presence of common physicochemical

properties such as electronegativity, steric size, and lipophilicity in all of them. The

other reason is the possibility of correlating these values to the observed biological

activity. These observations are consistent with the fact that bioisosteric replacements

often provide the foundation for the development of QSAR in drug design [4, 6].

Recent advances in molecular biology, such as cloning of the various receptor

subtypes, have enabled a clearer definition of the pharmacophoric sites. Bioisosteric

replacements of functional groups based on this understanding of the pharmacophore

and the physicochemical properties of the bioisosteres have enhanced the potential for

the successful development of new clinical agents. The critical component for

bioisosterism is that bioisosteres affect the same pharmacological target as agonists or

antagonists and, hence, have biological properties which are related to each other.


54

Imidazo[2,1-b][1,3,4] thiadiazole derivatives are one such class of compounds

which yield themselves well to bioisosteric replacement studies. These practically

planar and rigid heteroaromatic systems with two condensed heterocycles, with their

-conjugations, are best suited for modifications that result in compounds

with interesting medicinal properties. This is due to the fact that the

imidazothiadiazole ring is bioisosteric with the Imidazo[2,1-b]thiazole of the novel

broad spectrum anthelmintic ‘Tetramisole’ [7-9]. 1,3,4-thiadiazoles are known for

their promising biological and pharmacological activities, possibly due to the

presence pharmacophoric isothioamide (S–C=N-) unit in the thiadiazole

nucleus[10,11]. This fact, coupled with the reported anti-cancer properties of some

thiadiazoles [12], makes 1,3,4-thiadiazole derivatives, compounds with potential

pharmaceutical prospects.

After the discovery of tetramisole, the synthesis and biological activities of

many condensed imidazo[2,1- b][1,3,4]thiazoles were reported [8,9,13,14]. In

addition, drugs closely related to tetramisole have been investigated. In this regard,

many drugs containing the imidazo[2,1-b][1,3,4]thiadiazole ring system, are being

explored. Imidazole[2,1-b][1,3,4]thiadiazole derivatives have been of interest to the

medicinal chemists for many years because of their anticancer [15], antitubercular

[16], antibacterial [17,18], antifungal[19], anticonvulsant, analgesic [20] and

antisecretory [21] activities. This is due to the fact that the imidazole [2,1-b][1,3,4]

thiadiazole system is similar in part to Levamisole, a well-known immune modulator

[22, 23]. Moreover Mannich bases of many heterocycles are known for diverse

biological activities [24]. The authors have recently reported that Mannich bases of

imidazole [2,1-b][1,3,4] thiadiazoles possess considerable antitubercular and

antimicrobial activities [25]. One such Mannich reaction is discussed in this chapter.

Apart from this, fluorinated compounds in general and fluorinated heterocyclic

compounds in particular, are the focus of much interest in modern medicinal

chemistry. In other classes of antitumour compounds, e.g. the anthracycline

antibiotics [26], the substitution of a hydrogen atom for a fluorine atom in the

tetracyclic ring system was found to possess better antitumour properties [27]. In

recent years there have been reports that the incorporation of fluorine atom could alter

the course of the reaction as well as enhance the biological properties. Accumulation

of fluorine on carbon leads to increased oxidative and thermal stability. Thus


55

fluorinated drugs, being metabolically non-degradable, are regarded as useful

therapeutic agents. Further, such drugs have increased lipid solubility, resulting in an

increased rate of absorption and transport in vivo [28, 29].

In the light of these findings about the pharmacological significance of the

Imidazo[2,1-b][1,3,4] thiadiazole ring system, it was considered worthwhile to

synthesize its derivatives with pharmacophoric substituents, which may have

equally significant roles to play in biological systems. The structural elucidation of

these compounds was undertaken with the intention of correlating their structure and

activity. The study has revealed that certain structural features, namely the angular

orientation of imidazothiadiazole ring system with respect to other rings in the

molecule due to the orthogonal orientation of the fluorobenzyl with the imidazo-

thiadiazole ring, presence of a strong intramolecular hydrogen bond and the

conformational rigidity of the pseudo five-membered ring. as well as the C–H...O and

C-H…N hydrogen bond aided self assembly are found to be common to all of them.

Additionally, the X-ray analysis was carried out in order to establish supramolecular

assembly with the specific aim of assessing various weak interactions including

fluorine interaction that control the architecture of organic solids. The stabilization of

the structure due to intermolecular C-H…F, C-H…O and C-H…N interactions was

analyzed wherein the supramolecular aggregation in the molecule highlights a very

interesting molecular packing features on C-H…F interaction where the six molecules

connects themselves into a perfect hexagonal geometry depicting a cyclohexagonal

ring pattern in order to establish the construction of crystalline superstructures.

Structural comparison of all these compounds seems to point towards a unique

binding mode to proteins in biological systems, which necessitate the virtual

screening of these entities via docking studies.

Recent studies have demonstrated that these aromatic interactions can be

stabilized by fluorine substitution and used for generating molecular assemblies of

growing hierarchical complexity [30]. In the field of molecular based materials, all

these types of noncovalent interactions can be used to control both the resulting

molecular packing and solid state properties. In particular, it has been demonstrated

that supramolecular organizations can have a significant impact on the solid state

photophysical properties of luminescent inorganic complexes, as emission can be

quenched or enhanced by aggregation effects [31].


56

Section B: A general study on the role of Fluorine interaction

Fluorine is known for its odd behaviour in non-bonded interactions [32].

Fluorine atom is the most electronegative element and approximately isosteric to

oxygen. While inorganic fluoride ion is the most powerful proton-acceptor (its

strength of hydrogen bond is 40 kcal mol 1) [33] in staggering contrast the covalently

bound fluorine is a very weak intermolecular hydrogen bonding acceptor (strength of

X–F…H–Y hydrogen bond is 2–3.2 kcal mol 1 as compared to 5–10 kcal mol 1 for

H…O hydrogen bond, X and Y are covalently attached atoms) [34]. Indeed, fluorine

is considered to hardly ever form hydrogen bond. This anomalous behaviour of

fluorine has been attributed to many electrostatic and steric factors such as its low

polarizability and tightly contracted lone pairs [32-35]. On the basis of CSD studies,

concluded that the C-F group is unable to compete favorably with O and N atom

acceptors. This assumption is further reinforced by database and computational

studies of Howard and co-workers as well as Dunitz and Taylor which show C-F

group as a very poor acceptor with least propensity for hydrogen bond formation. It

has also been stated that the poor competition of the C-F group with O and N atom

acceptors extends to C-H donors, questioning the existence and nature of C-H...F

interaction [36].

In the backdrop of such generally held views on C-F group's weak acceptor

capability, an interesting structural excursion is provided by the analysis of the crystal

packing of the title compound. The self assembly in this case reveals that the

stabilization of crystalline architecture is solely due to C-H...F interactions in spite of

unavoidable competition from O and N acceptor atoms. This shows that the C-H...F

interaction is indeed a specific "hydrogen bond" type of interaction and not merely a

provider of van der Waals stabilization.

In recent years, a large number of structures containing fluorine have been reported.

Upon examination, it turns out that the role assigned to fluorine as ‘odd one out,’

based-on analysis of N–H…F and O–H…F interactions in the database [32, 33], is not

necessarily true. Several structures having significant role of C–H…F and C–F…

interactions have been observed. Even though these interactions involving fluorine are

much weaker than conventional N/O–H…O hydrogen bonds, their role in determining

the modes of molecular packing cannot be ignored [34, 36, 37]. Indeed, there are

reported examples that clearly demonstrate that weak fluorine interactions certainly

alter the packing modes [38]. Guru Row and co-workers have extensively studied the


57

structural property of fluorine and they have presented several elegant examples of

fluorine-directed crystal packing [38-41]. In recent years, fluorine has been shown to

influence non-bonded intermolecular association and ligand-receptor binding via

different modes of interactions such as steroelectronic effects, as observed in many

drug-receptor binding e.g., Prozac, Ciprofloxacin and Atorvastatin [42,44].

In C–H…F type interactions, the C–F bond acts as proton acceptor and it is

one of the predominant interactions in fluorine containing compounds and hence it is

considered as a tool for crystal engineering [44]. In the absence of any strong

hydrogen bond donor or acceptor, fluorine has shown its ability to form different

motifs such as dimer, chain, chains of dimers, tetramer, etc. via C—H…F--C and C—

F…F--C interactions. It has been shown that fluorine does not readily accept

hydrogen bonds and hence behaves differently from chlorine and bromine [45].

Organic fluorine packs significant number of compounds via weak interactions [46,

47] and generates different packing motifs via F-F, C-H…F and C-F interactions.

It is known [48] that substitution of fluorine for hydrogen in organic compounds

substantially affects not only the crystal structure, but also other physicochemical

properties.

In the past few years, efforts have been made to recognize interactions

involving halogen [49]. Although there are some debates that organic fluorine does

not contribute to the formation of hydrogen bonding and the crystal packing [50],

more and more studies demonstrate that organic fluorine can provide weak but

directional C H···F–C interactions between adjacent molecules to generate an

expansion of the supramolecular architectures [51].

Moreover presence of fluoro substituent in the molecule provides compound with

enhanced biological activity. Thus fluorine chemistry appears to claim the center

stage in chemical research in the last few years with a flood of crystal structures of

drugs and pharmaceuticals and a large number of supporting theoretical studies

aiming to unravel the features of interactions involving fluorine.

In this chapter the effect of fluoro substitution on the packing of the

imidazothiadiazole frameworks has been discussed. We chose the fluoro substituent

because it has a much smaller van der Waals radius than other substituents used

hitherto, while it is very similar to that of hydrogen. This allows a method to

distinguish between substituent effects due to size and those due to non-bonded


58

interactions on the crystal packing. It can be shown that intermolecular atom-atom

interactions involving the fluoro groups hold sway over the effect of the volume of the

subtituents upon crystal packing.

1.2. Interactions Involving Halogen Atoms

Intermolecular interactions involving halogens F, C1, Br and I continue to be

the subject of investigation, as halogens can form short non-bonded contacts with

electron acceptors as well as electron donors [52]. This behavior has been rationalized

based on anisotropic (non-spherical) charge distribution in halogen atoms [53]. Thus,

heavier halogens except fluorine, due to extreme electronegativity and limited

polarizability exhibit electrophilic character along the axis of C–X bonds and

nucleophilic character perpendicular to these bonds. Fluorine has been observed to

behave differently in an organic environment and its participation in intermolecular

interactions has always remained controversial. Thus, halogens can act as hydrogen-

bond donors or acceptors depending on the angle of approach. Hence, interactions of

halogens with nucleophiles (e.g. O, N) display roughly linear geometry with respect

to the halogens, whereas interaction with electrophiles occur in side-on fashion. Some

of the recognized weak intermolecular interactions involving halogen atoms are

mentioned in this chapter.

C–H···X (X = F, Cl, Br and I) type interactions were observed to occur when

halogen atom acts as hydrogen atom acceptor. However, the existence of C–H···Cl

hydrogen bonds has been questioned [54]. Gibb and co-workers [55] carried out a

systematic survey of Cambridge Crystal Structure Database, which established the

extensive occurrence of C–H···Cl hydrogen bonds. Furthermore, they showed that C–

H···X interactions are real and they do play an important role in molecular aggregation

and are useful for the prediction of crystal structure. It was observed that chloride

anions are better hydrogen bond acceptor systems than neutral chloride containing

molecules and a similar situation pertains for the other halides. The number of

occurrence of C–H···halogen bonding with F and Cl are more compared to that of

bromine and Iodine, probably because as the size of the halogen atom increases

(decrease in electronegativity) it becomes electron pair acceptor rather than donor

[55]. However, the ability of other halogen atoms to function as H-bond acceptors is

still under debate.


59

2.2. Crystal and molecular structure of 2-(4-Fluorobenzyl)-6-

phenylimidazo [2,1-b][1,3,4]thiadiazole (A1)

Fig: 2.1a.2.2.1. Introduction

The title compound A1 (C17H12FN3S), being an imidazo[2,1-b][1,3,4]thiadiazole

derivative, has promising biological and pharmacological activities. Secondly, the

thiadiazole ring is bioisosteric with the thiazole moiety of the novel broad spectrum

anthelmintic tetramisole. Some thiadiazole derivatives are reported to possess anti-

cancer properties. Accumulation of fluorine on carbon leads to increased oxidative

and thermal stability. A single crystal x-ray diffraction analysis was carried out for

this compound in order to establish the crystal as well as molecular structure and to

understand the self-aggregation in terms of possible intermolecular interactions.

2.2.2. Experimental Procedure for the Preparation of A1

A mixture of 5-(4-fluorobenzyl)-1,3,4-thiadiazol-2-amine (1) [56] (2.69g, 0.01mol)

and phenacyl bromide (2) (0.01mol) was refluxed in dry ethanol for 12 hrs. The

excess of solvent was distilled off and the solid hydrobromide salt that separated was

collected by filtration, suspended in water and neutralized by aqueous sodium

carbonate solution to get free base (3). It is well established that this reaction proceeds

via the intermediate iminothiadiazole which under reflux temperature spontaneously

undergoes dehydrocyclisation to form the desired fused heterocycle. It was then

filtered, washed with water, dried and recrystallized from ethyl acetate to afford white

needles with good yield 75% (2.98g) A1.

Br

H

O

N

S

N

N

F

HN

S

N

NH2

F

Na2CO3

3

+

21

Dry EtOH, 18hr

A1

Scheme 2A


60

2.2.3. X-Ray Structure Analysis

The X-ray diffraction data for the compound (A1) was collected on a Bruker Smart

CCD Area Detector System at I.I.Sc., Bangalore, using MoK (0.71073Å) radiation

for the crystal. The data were reduced using SAINTPLUS [57]. The structure was

solved by direct methods using SHELXS97 [58] and difference Fourier synthesis

using SHELXL97 [58]. The positions and anisotropic displacement parameters of all

non-hydrogen atoms were included in the full-matrix least-square refinement using

SHELXL97 [58] and the procedures were carried out for a few cycles until

convergence was reached. The H atoms were placed at calculated positions in the

riding model approximation (C—H 0.93Å); their temperature factors were set to 1.2

times those of the equivalent isotropic temperature factors of the parent atoms. All

other non-H atoms were refined anisotropically. Molecular diagrams were generated

using ORTEP [59] and the packing diagrams were generated using CAMERON [60].

The mean plane calculation was done using the program PARST [61].

Intensity data were collected up to a maximum of 27.00° for the compound in the –

A total of 13113 reflections were collected, resulting in 9234

independent reflections of which the number of reflections satisfying I I) criteria

were 7000. These were treated as observed. The R factor for observed data finally

converged to R = 0.0857 with wR2 = 0.2363 in the compound. The maximum and

minimum values of residual electron density were 2.870 and -0.687 eÅ-3.

2.2.4. Results and Discussion

Figure 2.1a shows the chemical diagram of the compound A1. Table 2.1a summarizes

the crystal data, intensity data collection and refinement details for the compound A1.

The atomic coordinates of the nonhydrogen atoms with their equivalent temperature

factors for the compound are presented in Table 2.2a. Anisotropic displacement

parameters are given in Table 2.3a. The corresponding bond lengths and angles are

given in Tables 2.4a. The torsion angles for the nonhydrogen atoms are listed in Table

2.5a. Table 2.6a shows the atomic coordinates and isotropic temperature factors for

the hydrogen atoms. The least-squares planes calculated using the programs PARST

[61] are tabulated in Table 2.7a. The intermolecular hydrogen bonds are listed in

Table 2.8a


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The space group to which the compound belongs is P-1. The compound (Fig 2.2a) has

three independent molecules in the asymmetric unit. The central imidazo-thiadiazole

unit is linked to fluorobenzyl group at one end and phenyl ring at the other. The

dihedral angles between fluorobenzyl and imidazo-thiadaizole rings is orthogonally

inclined at an angle 88.25(6)°/81.43(2)°/82.79(8)° (the three values corresponds to the

three independent molecules) and angles between imidazo-thiadiazole and phenyl

ring 8.65(3)°/10.21(6)°/10.21(6)° represent the co-planarity of the molecule.

Fig: 2.2a

ORTEP diagram of compound A1, showing 50% probability displacement

ellipsoids and the atom-numbering scheme

The average value of the bond distances is 1.388(6)Å while the exocyclic bond angles

[120.6(8)°] in the phenyl rings of the molecule have normal values which agree quite

well with the values reported in the literature for some analogous structures [62, 63].

The survey of the structure at a molecular level reveals usual geometrical parameters

for the S–C bond of 1.731(5)Å. The N–C and N-N bonds of the three independent

molecules A, B and C are 1.360(6)Å/1.354Å/1.358Å and 1.380Å/1.352(2)Å/1.375Å

respectively which are shorter than typical bond lengths -electron

delocalization. The C=N bond length of 1.310(7)Å confirms it as a double bond. The

orientation of fluorobenzyl group is characterized by torsion angles C(17A)-C(12A)-

C(1A)-C(2A) of 85.1(6)°, C(17B)-C(12B)-C(1B)-C(2B) of 83.7(5)° and C(13C)-

C(12C)-C(1C)-C(2C) of 86.0(6)° in molecules A, B and C respectively. The most

interesting feature of this compound is the analyses of the crystal packing indicating

intra and intermolecular interactions. All the three molecules in the asymmetric unit

are primarily stabilized by two strong intramolecular C-H…N hydrogen bonds in the

crystal structure.


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2.2.5. Intermolecular Features

The crystal structure of compound A1 is further stabilized by intermolecular C-H…N

and C-H…F hydrogen bonds. There are two C-H…N interactions, the former

generates bifurcated bonds from two donor atoms, C4 and C14 to the same acceptor,

N3 linking the dimers into tape like pattern while the latter leads to the formation of

centrosymmetric head to head dimers corresponding to graph set notation R22(14) [64]

along ‘a’ axis (Fig 2.3a). These C-H…N hydrogen bonds have been extensively used

in crystal engineering [65, 66].

Fig 2.3a: Packing of the molecules in crystal of A1 viewed along ‘a’ axis. Dotted lines indicate C-H...N intermolecular interactions resulting in dimers and

bifurcated bond.

The intermolecular C-H…F interaction of the molecule lead to two dimensional

supramolecular porous network of hexagonal hydrogen bond pattern in the crystal

structure where the six molecules connects themselves into a perfect cyclohexagonal

ring pattern along ‘a’ axis (Fig 2. 4a). The function of the C-F group in crystal

packing helps in the understanding of the binding of a fluorinated substrate to a

macromolecular receptor [67, 68]. The C-H…F interaction (3.284 Å) has least donor-

acceptor distance compared to C-H…N (3.536 Å), which makes the C-H…F bond a

successful competitor for the C-H donor. This is unusual since it happens in the

presence of oxygen and nitrogen which are strong acceptor atoms, thus making the C-

H...F interaction an important structure-directing entity. The molecular packing is

- between the benzene and

imidazothiadiazole ring systems with C2-C7 atoms of two molecules being separated

by a distance of 3.757(4)Å (symmetry code: ½-x, y, -z ) (Fig 2.5a) strengthening the


63

supramolecular assembly in the crystal structure. In the molecular packing of

compound A1, the C-H…F interactions play important role in the formation of the

supramolecular network influencing the conformation and property of imidazo-

thiadiazole derivatives.

Fig 2.4a: Packing of the molecules of A1 with dotted lines indicating C-H…Fintermolecular interactions generating hexagonal hydrogen bond along ‘a’ axis.

Fig. 2.5a

- A1


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Table 2.1aSummary of crystal data, intensity data collection and refinement of A1compound

Crystal dataC17H12FN3SMr = 309.36Triclinic, P-1a = 5.582 Åb = 20.888 Åc = 21.405 Å

= 117.06° = 94.81° = 94.89°

V = 2193.0 Å3

Z = 6

Data collectionBruker SMART CCD area - detector diffractometer

and scansAbsorption correction: none13113 measured reflections9234 independent reflections

RefinementRefinement on F2

R[F2 2)]= 0.0857wR(F2) = 0.280S = 1.1449234 reflections595 parameters

H atoms treated by a mixture of independent and constrained

refinement

Dx = 1.405 Mgm-3

= 1.91 - 27.00°µ = 0.231 mm1

T = 296(2) KPrism, yellow0.18 × 0.16 × 0.16 mm

7000Rint = 0.0413

max = 27.00°h = -k = -19 26l = -

w=1/[\s2(Fo2)+(0.1494P)2

+2.5052P] where P=(Fo2+2Fc2)/3'

max = 0.000

max = 2.870 e Å–3

min = -0.687 e Å–3

Programs usedData collection: SMART (Bruker, 1998);Cell refinement: SMART Data reduction: SAINT (Bruker, 1998); Structure solution: SHELXS97 (Sheldrick, 2008); Structure refinement: SHELXL97 (Sheldrick, 2008); Molecular graphics: PLUTON (Speck, 1997); ORTEP-3 (Farrugia, 1997);

CAMERON (Watkin et al., 1993); WinGX (Farrugia, 1999)

Data deposition

Crystallographic data for the structure reported here has been deposited with the Cambridge Data Centre. The deposition number is CCDC 787336.


65

Table 2.2aAtomic coordinates (× 104) and equivalent isotropic

displacement parameters (Å2× 103) of A1 ________________________________________________________________

Atom x y z U(eq) ________________________________________________________________

C(1A) -6944(8) 1862(2) 3012(2) 32(1) C(2A) -6486(7) 1221(2) 2352(2) 25(1) C(3A) -4744(7) 260(2) 1444(2) 24(1) C(4A) -7891(7) -187(2) 606(2) 24(1) C(5A) -5854(7) -1191(2) -303(2) 23(1) C(6A) -5973(7) -560(2) 390(2) 22(1) C(7A) -7688(7) -1401(2) -870(2) 26(1) C(8A) -7601(8) -1996(2) -1515(2) 29(1) C(9A) -5652(8) -2390(2) -1611(2) 26(1) C(10A) -3814(8) -2182(2) -1046(2) 28(1) C(11A) -3909(7) -1588(2) -398(2) 26(1) C(12A) -5090(8) 2023(2) 3638(2) 28(1) C(13A) -5523(8) 1705(3) 4075(2) 34(1) C(14A) -3779(9) 1799(3) 4615(3) 40(1) C(15A) -1588(8) 2211(3) 4705(2) 36(1) C(16A) -1105(8) 2549(3) 4300(2) 36(1) C(17A) -2908(8) 2443(2) 3761(2) 33(1) F(1A) 173(5) 2289(2) 5226(2) 53(1) N(1A) -8085(6) 885(2) 1788(2) 27(1) N(2A) -7072(6) 339(2) 1279(2) 23(1) N(3A) -3983(6) -283(2) 920(2) 25(1) S(1A) -3677(2) 899(1) 2307(1) 27(1) C(1B) 8605(7) 4005(2) 6749(2) 29(1) C(2B) 7495(7) 3998(2) 6075(2) 24(1) C(3B) 4816(7) 3911(2) 5088(2) 23(1) C(4B) 7473(7) 4289(2) 4578(2) 24(1) C(5B) 4466(7) 4115(2) 3531(2) 21(1) C(6B) 5191(7) 4101(2) 4204(2) 21(1) C(7B) 6095(7) 4430(2) 3258(2) 25(1) C(8B) 5412(8) 4426(2) 2615(2) 28(1) C(9B) 3137(8) 4125(2) 2248(2) 27(1) C(10B) 1486(8) 3816(2) 2515(2) 28(1) C(11B) 2147(7) 3811(2) 3157(2) 25(1) C(12B) 7053(8) 3490(2) 6920(2) 27(1) C(13B) 5266(8) 3742(2) 7352(2) 30(1) C(14B) 3623(8) 3265(3) 7452(2) 32(1) C(15B) 3861(8) 2540(2) 7114(2) 31(1) C(16B) 5669(9) 2276(3) 6706(3) 36(1) C(17B) 7263(9) 2759(3) 6609(2) 35(1) F(1B) 2262(5) 2056(2) 7193(2) 46(1) N(1B) 8738(6) 4225(2) 5710(2) 25(1) N(2B) 7202(6) 4170(2) 5153(2) 22(1) N(3B) 3511(6) 3860(2) 4521(2) 23(1) S(1B) 4402(2) 3709(1) 5777(1) 26(1) C(1C) -4930(8) 1867(2) 8629(3) 32(1) C(2C) -3816(7) 2594(2) 8714(2) 24(1) C(3C) -1135(7) 3599(2) 8778(2) 24(1)

C(4C) -3487(7) 4449(2) 9215(2) 24(1) C(5C) -481(7) 5461(2) 9247(2) 22(1) __________________________________________________________


66

Table 2.2a. (Contd.)__________________________________________________________

C(6C) -1320(7) 4717(2) 9106(2) 22(1) C(7C) -1766(7) 6032(2) 9627(2) 23(1) C(8C) -1040(8) 6732(2) 9744(2) 29(1) C(9C) 1037(8) 6885(2) 9491(2) 28(1) C(10C) 2345(7) 6325(2) 9115(2) 27(1) C(11C) 1579(7) 5621(2) 8994(2) 25(1) C(12C) -3700(8) 1256(2) 8137(3) 31(1) C(13C) -1630(8) 1075(3) 8395(3) 34(1) C(14C) -367(8) 552(2) 7954(3) 36(1) C(15C) -1221(9) 203(3) 7239(3) 41(1) C(16C) -3283(9) 348(3) 6958(3) 43(1) C(17C) -4516(8) 879(2) 7412(3) 36(1) F(1C) -4(6) -313(2) 6791(2) 60(1) N(1C) -4880(6) 3164(2) 8968(2) 25(1) N(2C) -3340(6) 3730(2) 8999(2) 23(1) N(3C) 166(6) 4179(2) 8829(2) 24(1) S(1C) -917(2) 2688(1) 8485(1) 26(1) ________________________________________________________________

Ueq i jUij(ai*aj*)(ai.aj)

Table 2.3aAnisotropic displacement parameters (Å2×103) of A1

The anisotropic displacement factor exponent takes the form:-2 2[ h2a*2U11+...+2hka*b*U12

_______________________________________________________________________

Atom U11 U22 U33 U23 U13 U12 _______________________________________________________________________

C(1A) 29(2) 32(2) 32(2) 11(2) 9(2) 10(2) C(2A) 24(2) 25(2) 30(2) 14(2) 5(2) 4(2) C(3A) 21(2) 27(2) 28(2) 16(2) 4(2) 6(2) C(4A) 18(2) 26(2) 26(2) 10(2) -3(1) 2(2) C(5A) 21(2) 26(2) 26(2) 17(2) 4(2) 1(2) C(6A) 20(2) 20(2) 25(2) 11(2) 0(1) 0(1) C(7A) 23(2) 23(2) 33(2) 15(2) 0(2) 1(2) C(8A) 26(2) 33(2) 29(2) 15(2) 1(2) 3(2) C(9A) 29(2) 22(2) 26(2) 10(2) 7(2) 3(2) C(10A) 24(2) 26(2) 34(2) 14(2) 9(2) 5(2) C(11A) 20(2) 27(2) 32(2) 15(2) 4(2) 4(2) C(12A) 25(2) 24(2) 29(2) 5(2) 7(2) 5(2) C(13A) 25(2) 34(2) 34(2) 9(2) 4(2) -5(2) C(14A) 41(3) 42(3) 33(2) 15(2) 8(2) 2(2) C(15A) 31(2) 39(2) 23(2) 3(2) 2(2) 1(2) C(16A) 26(2) 31(2) 36(2) 3(2) 11(2) -1(2) C(17A) 30(2) 27(2) 36(2) 10(2) 9(2) 4(2) F(1A) 35(2) 79(2) 31(2) 18(2) -3(1) -4(2) N(1A) 30(2) 25(2) 28(2) 11(2) 7(1) 10(1) N(2A) 20(2) 25(2) 28(2) 15(1) 5(1) 7(1) N(3A) 21(2) 27(2) 26(2) 11(1) 3(1) 4(1) S(1A) 23(1) 29(1) 26(1) 9(1) 2(1) 8(1) C(1B) 21(2) 36(2) 24(2) 11(2) -2(2) 3(2) _______________________________________________________________________


67

Table 2.3a. (Contd.)

C(2B) 24(2) 23(2) 24(2) 10(2) 6(2) 4(2) C(3B) 15(2) 22(2) 30(2) 12(2) 4(1) 1(1) C(4B) 22(2) 26(2) 23(2) 12(2) 1(2) -4(2) C(5B) 19(2) 15(2) 24(2) 6(2) 2(1) 3(1) C(6B) 18(2) 18(2) 29(2) 12(2) 3(1) 3(1) C(7B) 21(2) 26(2) 29(2) 13(2) 3(2) 5(2) C(8B) 27(2) 31(2) 31(2) 17(2) 7(2) 4(2) C(9B) 32(2) 27(2) 22(2) 11(2) -1(2) 5(2) C(10B) 24(2) 30(2) 26(2) 9(2) -1(2) 5(2) C(11B) 21(2) 26(2) 26(2) 12(2) 2(2) 4(2) C(12B) 26(2) 36(2) 21(2) 15(2) 1(2) 8(2) C(13B) 31(2) 35(2) 23(2) 12(2) 3(2) 8(2) C(14B) 31(2) 41(2) 30(2) 20(2) 12(2) 13(2) C(15B) 32(2) 34(2) 30(2) 17(2) 6(2) 4(2) C(16B) 44(3) 36(2) 36(2) 20(2) 18(2) 11(2) C(17B) 34(2) 42(3) 33(2) 19(2) 12(2) 15(2) F(1B) 44(2) 49(2) 57(2) 33(2) 18(1) 7(1) N(1B) 26(2) 25(2) 24(2) 11(1) 2(1) 1(1) N(2B) 16(2) 26(2) 24(2) 12(1) -2(1) 3(1) N(3B) 22(2) 26(2) 22(2) 12(1) 3(1) 4(1) S(1B) 20(1) 35(1) 26(1) 16(1) 1(1) 1(1) C(1C) 24(2) 33(2) 42(3) 21(2) 6(2) 1(2) C(2C) 17(2) 32(2) 28(2) 18(2) 2(2) -1(2) C(3C) 19(2) 34(2) 23(2) 16(2) 6(1) 5(2) C(4C) 22(2) 26(2) 26(2) 14(2) 6(2) 5(2) C(5C) 21(2) 26(2) 19(2) 13(2) -1(1) 2(2) C(6C) 22(2) 22(2) 20(2) 10(2) 3(1) 5(2) C(7C) 22(2) 27(2) 23(2) 13(2) 6(2) 4(2) C(8C) 27(2) 32(2) 28(2) 12(2) 5(2) 8(2) C(9C) 30(2) 26(2) 28(2) 14(2) -5(2) -2(2) C(10C) 20(2) 31(2) 31(2) 16(2) 1(2) 3(2) C(11C) 21(2) 27(2) 30(2) 17(2) 2(2) 3(2) C(12C) 21(2) 27(2) 49(3) 22(2) 5(2) 0(2) C(13C) 32(2) 34(2) 45(3) 28(2) -1(2) -3(2) C(14C) 24(2) 28(2) 62(3) 26(2) 4(2) 4(2) C(15C) 27(2) 27(2) 61(3) 13(2) 6(2) 2(2) C(16C) 38(3) 29(2) 46(3) 5(2) -8(2) 7(2) C(17C) 27(2) 29(2) 45(3) 14(2) -6(2) 3(2) F(1C) 40(2) 34(2) 81(2) 3(2) 4(2) 13(1) N(1C) 22(2) 24(2) 30(2) 15(2) 4(1) 1(1) N(2C) 18(2) 26(2) 25(2) 13(1) 5(1) 1(1) N(3C) 19(2) 29(2) 28(2) 16(2) 4(1) 5(1) S(1C) 21(1) 25(1) 34(1) 14(1) 8(1) 3(1)

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68

Table 2.4aBond lengths [Å] and angles [°] for non H-atoms of A1

with esds in parenthesis__________________________________________________________

C(1A)-C(2A) 1.502(6)C(1A)-C(12A) 1.509(6)C(2A)-N(1A) 1.300(5)C(2A)-S(1A) 1.750(4)C(3A)-N(3A) 1.314(5)C(3A)-N(2A) 1.362(5)C(3A)-S(1A) 1.729(4)C(4A)-N(2A) 1.362(5)C(4A)-C(6A) 1.365(5)C(5A)-C(11A) 1.394(5)C(5A)-C(7A) 1.395(5)C(5A)-C(6A) 1.481(6)C(6A)-N(3A) 1.393(5)C(7A)-C(8A) 1.383(6)C(8A)-C(9A) 1.392(6)C(9A)-C(10A) 1.394(6)C(10A)-C(11A) 1.387(6)C(12A)-C(17A) 1.370(6)C(12A)-C(13A) 1.395(7)C(13A)-C(14A) 1.377(7)C(14A)-C(15A) 1.380(7)C(15A)-F(1A) 1.364(5)C(15A)-C(16A) 1.375(7)C(16A)-C(17A) 1.387(7)N(1A)-N(2A) 1.375(5)C(1B)-C(2B) 1.515(6)C(1B)-C(12B) 1.516(6)C(2B)-N(1B) 1.297(5)C(2B)-S(1B) 1.743(4)C(3B)-N(3B) 1.317(5)C(3B)-N(2B) 1.365(5)C(3B)-S(1B) 1.734(4)C(4B)-C(6B) 1.370(5)C(4B)-N(2B) 1.379(5)C(5B)-C(7B) 1.393(6)C(5B)-C(11B) 1.394(5)C(5B)-C(6B) 1.477(5)C(6B)-N(3B) 1.391(5)C(7B)-C(8B) 1.395(6)C(8B)-C(9B) 1.368(6)C(9B)-C(10B) 1.385(6)C(10B)-C(11B) 1.397(6)C(12B)-C(17B) 1.380(6)C(12B)-C(13B) 1.389(6)C(13B)-C(14B) 1.397(7)C(14B)-C(15B) 1.374(6)C(15B)-F(1B) 1.369(5)C(15B)-C(16B) 1.374(6)C(16B)-C(17B) 1.386(7)N(1B)-N(2B) 1.363(4)C(1C)-C(12C) 1.503(6)C(1C)-C(2C) 1.513(6)

C(2C)-N(1C) 1.286(5)C(2C)-S(1C) 1.751(4)C(3C)-N(3C) 1.312(5)C(3C)-N(2C) 1.360(5)C(3C)-S(1C) 1.732(4)

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69

Table 2.4a. (Contd.)__________________________________________________________

C(4C)-N(2C) 1.367(5)C(4C)-C(6C) 1.372(6)C(5C)-C(11C) 1.390(6)C(5C)-C(7C) 1.399(5)C(5C)-C(6C) 1.466(5)C(6C)-N(3C) 1.393(5)C(7C)-C(8C) 1.383(6)C(8C)-C(9C) 1.392(6)C(9C)-C(10C) 1.392(6)C(10C)-C(11C) 1.394(6)C(12C)-C(13C) 1.393(6)C(12C)-C(17C) 1.394(7)C(13C)-C(14C) 1.373(7)C(14C)-C(15C) 1.379(7)C(15C)-F(1C) 1.356(6)C(15C)-C(16C) 1.374(7)C(16C)-C(17C) 1.382(7)N(1C)-N(2C) 1.374(5)

C(2A)-C(1A)-C(12A) 111.7(3)N(1A)-C(2A)-C(1A) 123.1(4)N(1A)-C(2A)-S(1A) 116.6(3)C(1A)-C(2A)-S(1A) 120.4(3)N(3A)-C(3A)-N(2A) 112.5(3)N(3A)-C(3A)-S(1A) 138.4(3)N(2A)-C(3A)-S(1A) 109.1(3)N(2A)-C(4A)-C(6A) 104.7(3)C(11A)-C(5A)-C(7A) 118.8(4)C(11A)-C(5A)-C(6A) 120.5(4)C(7A)-C(5A)-C(6A) 120.6(4)C(4A)-C(6A)-N(3A) 111.6(3)C(4A)-C(6A)-C(5A) 127.9(3)N(3A)-C(6A)-C(5A) 120.5(3)C(8A)-C(7A)-C(5A) 120.8(4)C(7A)-C(8A)-C(9A) 120.3(4)C(8A)-C(9A)-C(10A) 119.1(4)C(11A)-C(10A)-C(9A) 120.6(4)C(10A)-C(11A)-C(5A) 120.4(4)C(17A)-C(12A)-C(13A) 119.0(4)C(17A)-C(12A)-C(1A) 120.9(4)C(13A)-C(12A)-C(1A) 120.0(4)C(14A)-C(13A)-C(12A) 121.0(4)C(13A)-C(14A)-C(15A) 117.7(5)F(1A)-C(15A)-C(16A) 118.6(4)F(1A)-C(15A)-C(14A) 118.1(5)C(16A)-C(15A)-C(14A) 123.3(5)C(15A)-C(16A)-C(17A) 117.2(4)C(12A)-C(17A)-C(16A) 121.7(5)C(2A)-N(1A)-N(2A) 108.3(3)C(4A)-N(2A)-C(3A) 107.8(3)C(4A)-N(2A)-N(1A) 134.3(3)C(3A)-N(2A)-N(1A) 117.9(3)C(3A)-N(3A)-C(6A) 103.4(3)C(3A)-S(1A)-C(2A) 88.13(19)N(1B)-C(2B)-C(1B) 122.7(4)N(1B)-C(2B)-S(1B) 117.2(3)C(1B)-C(2B)-S(1B) 120.0(3)N(3B)-C(3B)-N(2B) 113.0(4)N(3B)-C(3B)-S(1B) 138.0(3)

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70

Table 2.4a. (Contd.)__________________________________________________________

N(2B)-C(3B)-S(1B) 109.0(3)C(6B)-C(4B)-N(2B) 104.6(3)C(7B)-C(5B)-C(11B) 118.9(4)C(7B)-C(5B)-C(6B) 120.4(3)C(11B)-C(5B)-C(6B) 120.7(4)C(4B)-C(6B)-N(3B) 111.8(3)C(4B)-C(6B)-C(5B) 127.1(4)N(3B)-C(6B)-C(5B) 121.0(3)C(5B)-C(7B)-C(8B) 120.0(4)C(9B)-C(8B)-C(7B) 120.9(4)C(8B)-C(9B)-C(10B) 119.8(4)C(9B)-C(10B)-C(11B) 120.0(4)C(5B)-C(11B)-C(10B) 120.4(4)C(17B)-C(12B)-C(13B) 119.3(4)C(17B)-C(12B)-C(1B) 120.8(4)C(13B)-C(12B)-C(1B) 119.8(4)C(12B)-C(13B)-C(14B) 121.0(4)C(15B)-C(14B)-C(13B) 117.5(4)F(1B)-C(15B)-C(14B) 119.1(4)F(1B)-C(15B)-C(16B) 118.0(4)C(14B)-C(15B)-C(16B) 122.9(4)C(15B)-C(16B)-C(17B) 118.5(4)C(12B)-C(17B)-C(16B) 120.8(4)C(2B)-N(1B)-N(2B) 108.2(3)N(1B)-N(2B)-C(3B) 118.0(3)N(1B)-N(2B)-C(4B) 134.9(3)C(3B)-N(2B)-C(4B) 107.1(3)C(3B)-N(3B)-C(6B) 103.5(3)C(3B)-S(1B)-C(2B) 87.68(19)C(12C)-C(1C)-C(2C) 111.8(4)N(1C)-C(2C)-C(1C) 122.9(4)N(1C)-C(2C)-S(1C) 117.2(3)C(1C)-C(2C)-S(1C) 119.8(3)N(3C)-C(3C)-N(2C) 112.8(4)N(3C)-C(3C)-S(1C) 138.5(3)N(2C)-C(3C)-S(1C) 108.6(3)N(2C)-C(4C)-C(6C) 104.7(3)C(11C)-C(5C)-C(7C) 117.6(4)C(11C)-C(5C)-C(6C) 121.3(4)C(7C)-C(5C)-C(6C) 121.0(4)C(4C)-C(6C)-N(3C) 111.4(3)C(4C)-C(6C)-C(5C) 128.5(4)N(3C)-C(6C)-C(5C) 120.2(4)C(8C)-C(7C)-C(5C) 121.7(4)C(9C)-C(10C)-C(11C) 120.2(4)C(5C)-C(11C)-C(10C) 121.3(4)C(13C)-C(12C)-C(1C) 120.2(4)C(17C)-C(12C)-C(1C) 121.5(4)C(14C)-C(13C)-C(12C) 121.8(5)C(13C)-C(14C)-C(15C) 117.8(4)F(1C)-C(15C)-C(16C) 118.0(5)F(1C)-C(15C)-C(14C) 119.1(4)

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71

Table 2.5aTorsion angles [°] for non H-atoms of A1 with esds in parenthesis_____________________________________________________________

C(12A)-C(1A)-C(2A)-N(1A) 165.2(4) C(12A)-C(1A)-C(2A)-S(1A) -16.1(5) N(2A)-C(4A)-C(6A)-N(3A) 1.1(5) N(2A)-C(4A)-C(6A)-C(5A) 180.0(4) C(11A)-C(5A)-C(6A)-C(4A) -168.8(4) C(7A)-C(5A)-C(6A)-C(4A) 11.0(7) C(11A)-C(5A)-C(6A)-N(3A) 10.0(6) C(7A)-C(5A)-C(6A)-N(3A) -170.2(4) C(11A)-C(5A)-C(7A)-C(8A) 0.7(6) C(6A)-C(5A)-C(7A)-C(8A) -179.1(4) C(5A)-C(7A)-C(8A)-C(9A) -1.1(7) C(7A)-C(8A)-C(9A)-C(10A) 1.0(7) C(8A)-C(9A)-C(10A)-C(11A) -0.7(6)

C(9A)-C(10A)-C(11A)-C(5A) 0.3(6) C(7A)-C(5A)-C(11A)-C(10A) -0.4(6) C(6A)-C(5A)-C(11A)-C(10A) 179.5(4) C(2A)-C(1A)-C(12A)-C(17A) 85.2(5) C(2A)-C(1A)-C(12A)-C(13A) -90.8(5) C(17A)-C(12A)-C(13A)-C(14A) -1.2(7) C(1A)-C(12A)-C(13A)-C(14A) 174.9(4) C(12A)-C(13A)-C(14A)-C(15A) -0.5(7) C(13A)-C(14A)-C(15A)-F(1A) -178.2(4) C(13A)-C(14A)-C(15A)-C(16A) 2.3(7) F(1A)-C(15A)-C(16A)-C(17A) 178.3(4) C(14A)-C(15A)-C(16A)-C(17A) -2.2(7) C(13A)-C(12A)-C(17A)-C(16A) 1.3(6) C(1A)-C(12A)-C(17A)-C(16A) -174.8(4) C(15A)-C(16A)-C(17A)-C(12A) 0.4(7) C(1A)-C(2A)-N(1A)-N(2A) 178.5(4) S(1A)-C(2A)-N(1A)-N(2A) -0.3(5)

C(6A)-C(4A)-N(2A)-C(3A) -0.8(5) C(6A)-C(4A)-N(2A)-N(1A) -179.5(4) N(3A)-C(3A)-N(2A)-C(4A) 0.3(5) S(1A)-C(3A)-N(2A)-C(4A) -177.9(3) N(3A)-C(3A)-N(2A)-N(1A) 179.2(4) S(1A)-C(3A)-N(2A)-N(1A) 1.0(5) C(2A)-N(1A)-N(2A)-C(4A) 178.0(4) C(2A)-N(1A)-N(2A)-C(3A) -0.5(5) N(2A)-C(3A)-N(3A)-C(6A) 0.3(5) S(1A)-C(3A)-N(3A)-C(6A) 177.7(4) C(4A)-C(6A)-N(3A)-C(3A) -0.9(5) C(5A)-C(6A)-N(3A)-C(3A) -179.9(4) N(3A)-C(3A)-S(1A)-C(2A) -178.4(5) N(2A)-C(3A)-S(1A)-C(2A) -0.9(3) N(1A)-C(2A)-S(1A)-C(3A) 0.7(4) C(1A)-C(2A)-S(1A)-C(3A) -178.0(4) C(12B)-C(1B)-C(2B)-N(1B) -160.3(4) C(12B)-C(1B)-C(2B)-S(1B) 22.0(5) N(2B)-C(4B)-C(6B)-N(3B) -0.8(4) N(2B)-C(4B)-C(6B)-C(5B) -178.9(4) C(7B)-C(5B)-C(6B)-C(4B) -9.1(6) C(11B)-C(5B)-C(6B)-C(4B) 170.7(4) C(11B)-C(5B)-C(6B)-N(3B) -7.2(5) C(11B)-C(5B)-C(7B)-C(8B) -1.2(6) C(6B)-C(5B)-C(7B)-C(8B) 178.6(4) C(5B)-C(7B)-C(8B)-C(9B) 1.0(6) C(7B)-C(8B)-C(9B)-C(10B) -0.3(6) C(8B)-C(9B)-C(10B)-C(11B) -0.1(6) C(7B)-C(5B)-C(11B)-C(10B) 0.8(6)

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72

Table 2.5a. (Contd.)__________________________________________________________

C(6B)-C(5B)-C(11B)-C(10B) -179.1(4) C(9B)-C(10B)-C(11B)-C(5B) -0.1(6) C(2B)-C(1B)-C(12B)-C(17B) 83.6(5) C(2B)-C(1B)-C(12B)-C(13B) -91.4(5) C(17B)-C(12B)-C(13B)-C(14B) -2.7(6) C(1B)-C(12B)-C(13B)-C(14B) 172.4(4) C(12B)-C(13B)-C(14B)-C(15B) 0.7(6) C(13B)-C(14B)-C(15B)-F(1B) -179.2(4) C(13B)-C(14B)-C(15B)-C(16B) 2.0(7) F(1B)-C(15B)-C(16B)-C(17B) 178.6(4) C(14B)-C(15B)-C(16B)-C(17B) -2.6(7) C(13B)-C(12B)-C(17B)-C(16B) 2.0(7) C(1B)-C(12B)-C(17B)-C(16B) -172.9(4) C(15B)-C(16B)-C(17B)-C(12B) 0.5(7) C(1B)-C(2B)-N(1B)-N(2B) -178.0(3) S(1B)-C(2B)-N(1B)-N(2B) -0.3(4) C(2B)-N(1B)-N(2B)-C(3B) 0.3(5) C(2B)-N(1B)-N(2B)-C(4B) -176.1(4) N(3B)-C(3B)-N(2B)-N(1B) -178.0(3) S(1B)-C(3B)-N(2B)-N(1B) -0.2(4) N(3B)-C(3B)-N(2B)-C(4B) -0.7(5) S(1B)-C(3B)-N(2B)-C(4B) 177.1(3) C(6B)-C(4B)-N(2B)-N(1B) 177.6(4) C(6B)-C(4B)-N(2B)-C(3B) 0.9(4) N(2B)-C(3B)-N(3B)-C(6B) 0.2(4) S(1B)-C(3B)-N(3B)-C(6B) -176.7(4) C(4B)-C(6B)-N(3B)-C(3B) 0.4(4) C(5B)-C(6B)-N(3B)-C(3B) 178.6(3) N(3B)-C(3B)-S(1B)-C(2B) 177.0(5) N(2B)-C(3B)-S(1B)-C(2B) 0.1(3) N(1B)-C(2B)-S(1B)-C(3B) 0.1(3) C(1B)-C(2B)-S(1B)-C(3B) 177.9(3) C(12C)-C(1C)-C(2C)-N(1C) 163.4(4) C(12C)-C(1C)-C(2C)-S(1C) -18.5(5) N(2C)-C(4C)-C(6C)-N(3C) -0.2(4) N(2C)-C(4C)-C(6C)-C(5C) -179.9(4) C(11C)-C(5C)-C(6C)-C(4C) -168.5(4) C(7C)-C(5C)-C(6C)-C(4C) 9.8(6) C(11C)-C(5C)-C(6C)-N(3C) 11.8(6) C(7C)-C(5C)-C(6C)-N(3C) -169.8(3) C(11C)-C(5C)-C(7C)-C(8C) 0.5(6) C(6C)-C(5C)-C(7C)-C(8C) -177.8(4) C(5C)-C(7C)-C(8C)-C(9C) -1.0(6) C(7C)-C(5C)-C(11C)-C(10C) 0.2(6) C(6C)-C(5C)-C(11C)-C(10C) 178.6(4) C(9C)-C(10C)-C(11C)-C(5C) -0.4(6) C(2C)-C(1C)-C(12C)-C(13C) 86.1(5) C(2C)-C(1C)-C(12C)-C(17C) -91.0(5) C(17C)-C(12C)-C(13C)-C(14C) 1.5(7) C(1C)-C(12C)-C(13C)-C(14C) -175.7(4) C(12C)-C(13C)-C(14C)-C(15C) -0.3(7) C(13C)-C(14C)-C(15C)-F(1C) 179.7(4) C(13C)-C(14C)-C(15C)-C(16C) -1.1(8) F(1C)-C(15C)-C(16C)-C(17C) -179.4(5) C(14C)-C(15C)-C(16C)-C(17C) 1.4(8) C(15C)-C(16C)-C(17C)-C(12C) -0.1(8) C(1C)-C(2C)-N(1C)-N(2C) 177.6(4) S(1C)-C(2C)-N(1C)-N(2C) -0.6(4) N(3C)-C(3C)-N(2C)-C(4C) -0.6(5) S(1C)-C(3C)-N(2C)-C(4C) -178.9(3) _______________________________________________________


73

Table 2.5a. (Contd.)

__________________________________________________________

N(3C)-C(3C)-N(2C)-N(1C) 179.7(3) S(1C)-C(3C)-N(2C)-N(1C) 1.4(4)

C(2C)-N(1C)-N(2C)-C(4C) 179.8(4) N(2C)-C(3C)-N(3C)-C(6C) 0.5(4) S(1C)-C(3C)-N(3C)-C(6C) 178.1(4) C(4C)-C(6C)-N(3C)-C(3C) -0.2(4) C(5C)-C(6C)-N(3C)-C(3C) 179.6(3) N(3C)-C(3C)-S(1C)-C(2C) -179.0(5) N(2C)-C(3C)-S(1C)-C(2C) -1.3(3) N(1C)-C(2C)-S(1C)-C(3C) 1.2(3) C(1C)-C(2C)-S(1C)-C(3C) -177.1(4)

_____________________________________________________________

Table 2.6aHydrogen coordinates (× 104) and isotropic

displacement parameters (Å2×103) of A1 ________________________________________________________________

Atom x y z U(eq) ________________________________________________________________ H(1A1) -8553 1767 3117 38 H(1A2) -6895 2285 2933 38 H(4A) -9419 -273 350 29 H(7A) -8986 -1137 -814 31 H(8A) -8851 -2134 -1886 35 H(9A) -5578 -2786 -2046 31 H(10A) -2513 -2445 -1103 33 H(11A) -2667 -1453 -25 31 H(13A) -7012 1427 4000 41 H(14A) -4068 1591 4910 48 H(16A) 369 2838 4383 44 H(17A) -2628 2663 3477 39 H(1B1) 8762 4493 7138 34 H(1B2) 10216 3864 6694 34 H(4B) 8890 4459 4469 29 H(7B) 7639 4644 3505 31 H(8B) 6519 4632 2432 34 H(9B) 2700 4128 1820 33 H(10B) -63 3611 2268 34 H(11B) 1033 3603 3335 30 H(13B) 5161 4237 7579 36 H(14B) 2413 3431 7737 38 H(16B) 5819 1784 6499 43 H(17B) 8489 2589 6332 42 H(1C1) -4803 1879 9089 38 H(1C2) -6640 1781 8446 38 H(4C) -4772 4700 9396 28 H(7C) -3142 5938 9805 28

H(8C) -1940 7100 9991 35 H(9C) 1544 7356 9573 34 H(10C) 3735 6422 8944 32 H(11C) 2463 5251 8739 30 H(13C) -1088 1315 8879 41 H(14C) 1019 438 8131 43 H(16C) -3833 96 6475 52 H(17C) -5913 985 7232 43

_______________________________________________________________


74

Table 2.7aMean planes through various groups of atoms and deviations (Å) from the plane, in A1

The equation of the plane: m1X+m2Y+m3Z-D = 0 where m1, m2, m3 and D are constant. Starred atoms are included in the plane calculations.

Plane m1 m2 m3 D Atom Deviations

1 0.510(2) -0.585(2) -0.630(2) -6.655(1)C12*C13*O14*C15*C16*C17*

0.0092(4)-0.0053(5)-0.0086(5)0.0137(5)

-0.0075(5) -0.0053(3)

2 0.318(1) 0.886(6) -0.335(8) -2.668(5) C2* S1* C3* N3* C6* C4* N2* N1*

0.0025(5)-0.0018(1)0.0211(5)0.0079(4)-0.0061(4)-0.0208(5)0.0089(4)0.0045(4)

3 0.472(2) 0.829(2) -0.296(2) -3.054(6)C5*C7*C8*C9*C10*C11*

-0.0014(4)0.0036(5)-0.0052(5)0.0032(5)-0.0011(5)0.0002(4)

Dihedral angles formed by LSQ-Planes in A1

Plane1 Plane2 Angle

Imidazothiadiazole ring Fluorobenzyl 88.25(6)°

Imidazothiadiazole ring Phenyl ring 10.21(6)°


75

Table 2.8aNonbonded interactions and possible hydrogen bonds in A1 (Å, °)

(D-donor; A-Acceptor; H-hydrogen)

D–H...A D–H H...A D...A D–H...A

C16a–H16a...N3b

C14b-H14b...N3c

C4a-H4a....N3ai

C14c-H14c...N3aii

C17c-H17c...F1bi

C13a-H13a...F1ciii

C17b-H17b...F1aiv

C7b-H7b...N1bv

0.930(5)

0.930(5)

0.930(6)

0.930(6)

0.930(6)

0.930(5)

0.930(6)

0.930(4)

2.537(4)

2.641(4)

2.917(4)

2.663(4)

2.570(4)

2.523(3)

2.445(4)

2.740(3)

3.434(7)

3.536(6)

3.527(6)

3.536(8)

3.344(8)

3.351(6)

3.284(7)

3.607(5)

162

162

124

156

141

148

150

155

Symmetry code: (0) x, y, z (i) x-1, +y, +z (ii) -x,-y,-z+1 (iii) -x-1,-y,-z+1 (iv) x+1,+y,+z (v) -x+2,-y+1,-z+1


76

2.3. Crystal and molecular Structure of 2-(4-Fluorobenzyl)-6-(4-

methoxyphenyl)-5-morpholin-1-ylmethylimidazo[2,1-

b][1,3,4]thiadiazole (A2)

Fig: 2.1b

2.3.1. Introduction

The title compound A2 (C23H23FN4O2S), is one of the series of Imidazo[2,1-b][1.3.4]

thiadiazole derivatives with pharmacophoric substituent. The Mannich reaction has

been used to prepare this morpholinomethyl derivative which is known for its

promising biological and pharmacological activities. Moreover presence of

fluorinated heterocyclic compounds in particular, is the focus of much interest in

modern medicinal chemistry and enhances the biological properties. This compound

was synthesized and its structural study was undertaken with an intention that it may

be of help in correlating its therapeutic action to its structure.

2.3.2. Experimental procedure for the preparation of A2

A mixture of 2-(4-Fluorobenzyl)-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]

thiadiazole (2) (2.19g, 0.005mol), morpholine (0.87g, 0.01mol), formalin (1mL) and

acetic acid (1mL) in methanol (20mL) was refluxed for 10 hrs (monitored by TLC).

Reaction mixture was diluted with water and extracted with chloroform (3x30mL).

The combined chloroform extract was washed with water (3x30mL) and dried over

anhydrous sodium sulfate. The solvent was removed under vacuum and the residue

was recrystallized from benzene and hexane mixture to afford yellow crystalline solid

A2. Yield 85% (2.16g)


77

A2

The synthetic pathway used for the synthesis of compound A2 is outlined in Scheme 2B.

Scheme 2B


The X-ray diffraction data, for the compound was collected on a Bruker Smart CCD

Area Detector System at I.I.Sc., Bangalore, using MoK (0.71073Å) radiation for the

crystal. The data were reduced using SAINTPLUS [57]. The structure was solved by

direct methods using SHELXS97 [58] and difference Fourier synthesis using

SHELXL97 [58]. The positions and anisotropic displacement parameters of all non-

hydrogen atoms were included in the full-matrix least-square refinement using

SHELXL97 [58] and the procedures were carried out for a few cycles until

convergence was reached. The H atoms were placed at calculated positions in the

riding model approximation (C—H 0.93Å); their temperature factors were set to 1.2

times those of the equivalent isotropic temperature factors of the parent atoms. All

other non-H atoms were refined anisotropically. Molecular diagrams were generated

using ORTEP [59] and the packing diagrams were generated using CAMERON [60].



scan mode. A total of 5430 reflections were collected, resulting in 3631 independent

reflections of which the number of reflections satisfying I I) criteria were 2768.

These were treated as observed. The R factor after final convergence was 0.0547 and

the maximum and minimum values of residual electron density were 0.532 and –

0.326 eÅ-3.


78


Figure 3.1b shows the chemical diagram of the compound studied. Table 3.1b

summarizes the crystal data, intensity data collection and refinement details for the

compound A2. The atomic coordinates of the nonhydrogen atoms with their

equivalent temperature factors for the compound are presented in Table 3.2b

anisotropic displacement parameters are given in Table 3.3b. The corresponding bond

lengths and angles are given in Tables 3.4b. The torsion angles for the nonhydrogen

atoms are listed in Table 3.5b. Table 3.6b shows the atomic coordinates and isotropic

temperature factors for the hydrogen atoms. The least-squares planes calculated using

the programs PARST [61] are tabulated in Table 3.7b. The intermolecular hydrogen

bonds are listed in Table 3.8b.

Fig: 2.2b


ellipsoids and the atom-numbering scheme.

Molecule A2 (Fig.2.2b) crystallizes in triclinic space group P-1. The presence of

morpholinomethyl ring decreases the planarity of the molecule. This can be seen in

the angle between imidazo-thiadiazole and methoxyphenyl rings increasing to 17.45°

and that between fluorobenzyl and imidazo-thiadiazole increasing to 79.21°. The

morpholinomethyl ring is almost orthogonal to imidazo-thiadiazole ring at an angle of

85.58°. A weak intramolecular C-H...N hydrogen bond interaction, which forms an

S(7) graph-set motif, helps to establish the relative conformations of the ring systems

involved. The morpholinomethyl moiety adopts a conventional chair conformation


79

with oxygen and nitrogen atoms deviating from the plane and occupying apical and

base positions respectively. The bond lengths and angles in morpholinomethyl ring

conform to standard values [69].


In the crystal structure, there are C-H…O, C-H…N and C-H…F interactions. The C-

H…O interaction generates a bifurcated bond from two donors, C11 and C13 to the

same acceptor, O2 connecting the molecules into chain along the ‘b’ axis (Fig 2.3b).

Further, the C-H…N interactions also result in bifurcated bond from two donors, C17

and C23 to the same acceptor, N3 linking the dimers so formed into a tape pattern

along the ‘c’ axis (Fig 2.4b).

But the donor-acceptor distance is least in the C-H…F interaction (3.517 Å)

compared to those in C-H…O (3.525 Å) and C-H…N (3.457 Å), this makes the C-

H…F bond a successful competitor for the C-H donor. This is unusual since it

happens in the presence of oxygen and nitrogen which are strong acceptor atoms, thus

making the C-H...F interaction an important structure-directing entity. The molecules

are linked by paired C-H...F hydrogen bonds into cyclic dimers corresponding to

graph set [64] notation R22(28) (Fig.2.5b).

Fig 2.3b:Packing of the molecules of A2 with dotted lines indicating C-H…O

intermolecular interactions generating bifurcated bond along ‘b’ axis.


80

Fig 2.4b: View of the molecular packing in, showing C-H…N interactions along‘c’ axis in A2

Fig 2.5b: The C-H...F dimers in crystal structure of A2 viewed along 'b' axis.

- between

fluorobenzyl rings with the shortest centroid- -

C13 carbons [Cg-Cg symmetry code: -x, 1-y, 1-z]. Notably, there are no F...F

contacts, which show fluorine would form C-H...F interactions rather than F...F

contacts. This distinctly different behavior of F from other heavier halogens which


81

prefer halogen-halogen interactions has been observed in many organo fluorine

compounds [70-72]

The presence of fluorine atoms attached to the aromatic ring increases the

acidity of the aromatic hydrogen atoms as is generally observed with aromatic

compounds [73] and the strength of any C-H...X interaction (X =halogen) depends on

C-H group acidity. Regarding the location of the F atom, the flourobenzyl group is

attached to the thiadiazole part of imidazo-thiadiazole system. It is well known that

fused nature. The imidazole part of this imidazo-thiadiazole system is more resonance

stabilized. Additionally, the imidazo-thiadiazole entity is generally planar and rigid.

The crystal packing of compound, establishes the fact that the so-called

elusive C-H...F interaction can be as important as C-H...O and C-H...N interactions in

achieving a cohesive self assembly. Supramolecular synthons based on this weak

interaction can be useful building blocks for construction of crystalline

superstructures. The prospects for such systematic design of structures are worth

exploring.

Fig. 2.6b

- A2


82

Table 2.1bSummary of crystal data, intensity data collection and refinement of A2 compound

Crystal dataC23H23FN4O2SMr = 438.51Triclinic, P-1

a = 7.4400(9)Å b = 10.5011(13) Å c = 14.2403(18)Å = 88.108(2)° = 80.189(2)° = 72.735(2)° V = 1046.7(2) Å3

Z = 2






refinement

Dx = 1.391 Mgm-3

= 2.03 - 25.00 °µ = 0.192 mm-1

T = 293 (2) K Prism, white0.4 × 0.35 × 0.3 mm

2768Rint = 0.0244

max = 25.00°h = -8k = -l = -

w = 1/[\s2(Fo2)+(0.1106P)2

+0.0000P] where P=(Fo2+2Fc

2)/3'

max = 0.001

max = 0.532 eÅ–3

min = -0.326 eÅ–3

Programs usedData collection: SMART (Bruker, 1998);Cell refinement: SMART; Data reduction: SAINT (Bruker, 1998); Structure solution: SHELXS97 (Sheldrick, 2008); Structure refinement: SHELXL97 (Sheldrick, 2008); Molecular graphics: PLUTON (Speck, 1997); ORTEP-3 (Farrugia, 1997);


Data deposition



83

Table 2.2bAtomic coordinates (× 104) and equivalent isotropic


Atom x y z U(eq) ________________________________________________________________

C(1) 12509(4) 2143(3) -59(2) 23(1) C(2) 12181(4) 1166(3) 566(2) 23(1) C(3) 10337(4) 1252(3) 1015(2) 23(1) C(4) 8774(4) 2297(3) 817(2) 21(1) C(5) 9142(4) 3251(3) 169(2) 23(1) C(6) 10984(4) 3191(3) -264(2) 23(1) C(7) 6827(4) 2418(3) 1307(2) 21(1) C(8) 6156(4) 1459(3) 1823(2) 21(1) C(9) 3888(4) 3407(3) 1849(2) 21(1) C(10) 1304(4) 2791(3) 2854(2) 21(1) C(11) -558(4) 2726(3) 3407(2) 24(1) C(12) -1894(4) 4075(3) 3763(2) 22(1) C(13) -1855(4) 4567(3) 4648(2) 23(1) C(14) -3064(4) 5790(3) 4989(2) 27(1) C(15) -4318(4) 6515(3) 4428(2) 25(1) C(16) -4399(4) 6088(3) 3550(2) 29(1) C(17) -3165(4) 4845(3) 3209(2) 25(1) C(18) 6986(4) -3(3) 1946(2) 23(1) C(19) 6877(4) -84(3) 3655(2) 24(1) C(20) 8062(4) -448(3) 4443(2) 27(1) C(21) 10419(4) -2041(3) 3439(2) 32(1) C(22) 9251(4) -1739(3) 2648(2) 29(1) C(23) 14839(5) 3035(3) -970(2) 33(1) S(1) 1534(1) 4265(1) 2273(1) 24(1) F(1) -5553(3) 7714(2) 4763(1) 38(1) O(1) 14386(3) 1969(2) -447(1) 26(1) O(2) 9222(3) -1801(2) 4351(1) 31(1) N(1) 2823(3) 1773(2) 2741(2) 22(1) N(2) 4263(3) 2134(2) 2166(2) 20(1) N(3) 5391(3) 3639(2) 1327(2) 23(1) N(4) 8101(3) -329(2) 2720(2) 20(1) ________________________________________________________________



84

Table 2.3bAnisotropic displacement parameters (Å2×103) of A2

The anisotropic displacement factor exponent takes the form:-2 2[ h2a*2U11+...+2hka*b*U12 ].

_______________________________________________________________________

Atom U11 U22 U33 U23 U13 U12 _______________________________________________________________________

C(1) 22(2) 26(2) 20(1) -7(1) -2(1) -7(1) C(2) 22(2) 23(2) 22(1) -2(1) -4(1) -3(1) C(3) 25(2) 24(2) 20(1) -1(1) -3(1) -8(1) C(4) 20(2) 26(2) 16(1) -3(1) -2(1) -7(1) C(5) 19(2) 23(2) 24(2) -2(1) -4(1) -2(1) C(6) 24(2) 22(2) 22(1) 1(1) -2(1) -7(1) C(7) 20(2) 21(1) 19(1) -1(1) -3(1) -3(1) C(8) 20(2) 22(2) 20(1) -1(1) -4(1) -3(1) C(9) 23(2) 20(1) 19(1) -1(1) -3(1) -3(1) C(10) 19(2) 22(2) 21(1) -2(1) -3(1) -4(1) C(11) 23(2) 23(2) 26(2) -2(1) -1(1) -5(1) C(12) 16(1) 22(2) 27(2) 1(1) 0(1) -7(1) C(13) 24(2) 23(2) 24(2) 4(1) -7(1) -8(1) C(14) 29(2) 28(2) 26(2) -4(1) -2(1) -14(1) C(15) 21(2) 19(1) 33(2) -1(1) 4(1) -4(1)

C(16) 23(2) 29(2) 33(2) 6(1) -4(1) -4(1) C(17) 23(2) 31(2) 21(2) -1(1) -1(1) -8(1) C(18) 23(2) 19(1) 26(2) -1(1) -5(1) -6(1) C(19) 22(2) 21(2) 28(2) 2(1) -5(1) -5(1) C(20) 28(2) 23(2) 26(2) 2(1) -6(1) 0(1) C(21) 28(2) 26(2) 34(2) 3(1) -2(1) 4(1) C(22) 26(2) 25(2) 29(2) -1(1) -1(1) -2(1) S(1) 21(1) 21(1) 28(1) 1(1) -2(1) -3(1) F(1) 39(1) 23(1) 44(1) -3(1) 5(1) -2(1) O(1) 19(1) 28(1) 29(1) -1(1) 1(1) -6(1) O(2) 32(1) 24(1) 31(1) 5(1) -5(1) 1(1) N(1) 21(1) 24(1) 23(1) 3(1) -6(1) -9(1) N(2) 18(1) 23(1) 19(1) 2(1) 0(1) -7(1) N(3) 24(1) 20(1) 24(1) 2(1) -7(1) -4(1) N(4) 20(1) 19(1) 21(1) 1(1) -2(1) -4(1) ____________________________________________________________________

Table 2.4bBond lengths [Å] and angles [°] for non H-atoms of A2

with esds in parenthesis._____________________________________________________________

S(1)-C(9) 1.727(3)S(1)-C(10) 1.770(3)F(1)-C(15) 1.364(3)O(1)-C(1) 1.372(3)O(1)-C(23) 1.416(4)O(2)-C(20) 1.424(3)O(2)-C(21) 1.428(4)N(1)-C(10) 1.295(3)N(1)-N(2) 1.373(3)N(2)-C(9) 1.361(3)N(2)-C(8) 1.386(3)N(3)-C(9) 1.314(4)N(3)-C(7) 1.401(3)

_____________________________________________________________


85

Table 2.4b. (Contd.)_________________________________________________________

N(4)-C(18) 1.462(3)N(4)-C(19) 1.462(3)N(4)-C(22) 1.470(3)C(1)-C(2) 1.384(4)C(1)-C(6) 1.391(4)C(2)-C(3) 1.390(4)C(3)-C(4) 1.403(4)C(4)-C(5) 1.395(4)C(4)-C(7) 1.467(4)C(5)-C(6) 1.388(4)C(7)-C(8) 1.388(4)C(8)-C(18) 1.492(4)C(10)-C(11) 1.491(4)C(11)-C(12) 1.514(4)C(12)-C(13) 1.385(4)C(12)-C(17) 1.389(4)C(13)-C(14) 1.379(4)C(14)-C(15) 1.371(4)C(15)-C(16) 1.359(4)C(16)-C(17) 1.401(4)C(19)-C(20) 1.514(4)C(21)-C(22) 1.507(4)

C(9)-S(1)-C(10) 88.00(13)C(1)-O(1)-C(23) 117.5(2)C(20)-O(2)-C(21) 110.3(2)C(10)-N(1)-N(2) 108.5(2)C(9)-N(2)-N(1) 118.3(2)C(9)-N(2)-C(8) 108.5(2)N(1)-N(2)-C(8) 133.2(2)C(9)-N(3)-C(7) 104.0(2)C(18)-N(4)-C(19) 111.7(2)C(18)-N(4)-C(22) 110.3(2)C(19)-N(4)-C(22) 108.6(2)O(1)-C(1)-C(2) 115.2(2)O(1)-C(1)-C(6) 124.7(3)C(2)-C(1)-C(6) 120.0(3)C(1)-C(2)-C(3) 120.2(3)C(2)-C(3)-C(4) 120.8(3)C(5)-C(4)-C(3) 117.7(3)C(5)-C(4)-C(7) 121.0(2)C(3)-C(4)-C(7) 121.3(3)C(6)-C(5)-C(4) 121.8(3)C(5)-C(6)-C(1) 119.3(3)C(8)-C(7)-N(3) 111.5(2)C(8)-C(7)-C(4) 128.2(2)N(3)-C(7)-C(4) 120.3(2)N(2)-C(8)-C(7) 103.5(2)N(2)-C(8)-C(18) 122.5(2)C(7)-C(8)-C(18) 133.7(3)N(3)-C(9)-N(2) 112.5(2)N(3)-C(9)-S(1) 138.4(2)N(2)-C(9)-S(1) 109.1(2)N(1)-C(10)-C(11) 122.6(3)N(1)-C(10)-S(1) 116.0(2)C(11)-C(10)-S(1) 121.3(2)C(10)-C(11)-C(12) 113.5(2)C(13)-C(12)-C(17) 118.9(3)C(13)-C(12)-C(11) 120.3(2)C(17)-C(12)-C(11) 120.8(3)

_______________________________________________________


86

Table 2.4b. (Contd.)_________________________________________________________

C(14)-C(13)-C(12) 121.3(3)C(15)-C(14)-C(13) 118.2(3)C(16)-C(15)-F(1) 118.1(3)C(16)-C(15)-C(14) 122.9(3)F(1)-C(15)-C(14) 119.0(3)C(15)-C(16)-C(17) 118.5(3)C(12)-C(17)-C(16) 120.1(3)N(4)-C(18)-C(8) 113.7(2)N(4)-C(19)-C(20) 110.7(2)O(2)-C(20)-C(19) 111.3(2)O(2)-C(21)-C(22) 111.1(2)N(4)-C(22)-C(21) 109.3(2)

_____________________________________________________________

Table 2.5bTorsion angles [°] for non H-atoms of A2 with esds in parenthesis

________________________________________________________________

C(10)-N(1)-N(2)-C(9) 0.9(3)C(10)-N(1)-N(2)-C(8) 179.4(3)C(23)-O(1)-C(1)-C(2) -170.3(2)C(23)-O(1)-C(1)-C(6) 10.8(4)O(1)-C(1)-C(2)-C(3) 178.9(2)C(6)-C(1)-C(2)-C(3) -2.2(4)C(1)-C(2)-C(3)-C(4) 2.5(4)C(2)-C(3)-C(4)-C(5) -1.0(4)C(2)-C(3)-C(4)-C(7) -178.3(2)C(3)-C(4)-C(5)-C(6) -0.6(4)C(7)-C(4)-C(5)-C(6) 176.6(2)C(4)-C(5)-C(6)-C(1) 0.9(4)O(1)-C(1)-C(6)-C(5) 179.4(2)C(2)-C(1)-C(6)-C(5) 0.5(4)C(9)-N(3)-C(7)-C(8) 0.0(3)C(9)-N(3)-C(7)-C(4) -177.4(2)C(5)-C(4)-C(7)-C(8) 166.7(3)C(3)-C(4)-C(7)-C(8) -16.2(4)C(5)-C(4)-C(7)-N(3) -16.4(4)C(3)-C(4)-C(7)-N(3) 160.7(2)C(9)-N(2)-C(8)-C(7) 0.6(3)N(1)-N(2)-C(8)-C(7) -178.1(3)C(9)-N(2)-C(8)-C(18) -173.1(2)N(1)-N(2)-C(8)-C(18) 8.3(4)N(3)-C(7)-C(8)-N(2) -0.4(3)C(4)-C(7)-C(8)-N(2) 176.7(2)N(3)-C(7)-C(8)-C(18) 172.2(3)C(4)-C(7)-C(8)-C(18) -10.7(5)C(7)-N(3)-C(9)-N(2) 0.4(3)C(7)-N(3)-C(9)-S(1) 179.2(3)N(1)-N(2)-C(9)-N(3) 178.3(2)C(8)-N(2)-C(9)-N(3) -0.6(3)N(1)-N(2)-C(9)-S(1) -0.9(3)C(8)-N(2)-C(9)-S(1) -179.79(17)C(10)-S(1)-C(9)-N(3) -178.4(3)C(10)-S(1)-C(9)-N(2) 0.47(19)

N(2)-N(1)-C(10)-C(11) 177.2(2)N(2)-N(1)-C(10)-S(1) -0.5(3)C(9)-S(1)-C(10)-N(1) 0.0(2)C(9)-S(1)-C(10)-C(11) -177.7(2)N(1)-C(10)-C(11)-C(12) 158.3(3)

________________________________________________________________


87

Table 2.5b. (Contd.)_________________________________________________________________

S(1)-C(10)-C(11)-C(12) -24.1(3)C(10)-C(11)-C(12)-C(13) -90.2(3)C(10)-C(11)-C(12)-C(17) 89.3(3)C(17)-C(12)-C(13)-C(14) 0.8(4)C(11)-C(12)-C(13)-C(14) -179.7(3)C(12)-C(13)-C(14)-C(15) 0.0(4)C(13)-C(14)-C(15)-C(16) -0.9(5)C(13)-C(14)-C(15)-F(1) 178.6(2)F(1)-C(15)-C(16)-C(17) -178.6(2)C(14)-C(15)-C(16)-C(17) 0.9(5)C(13)-C(12)-C(17)-C(16) -0.8(4)C(11)-C(12)-C(17)-C(16) 179.7(3)C(15)-C(16)-C(17)-C(12) 0.0(5)C(19)-N(4)-C(18)-C(8) 73.2(3)C(22)-N(4)-C(18)-C(8) -165.9(2)N(2)-C(8)-C(18)-N(4) -100.8(3)C(7)-C(8)-C(18)-N(4) 87.7(4)C(18)-N(4)-C(19)-C(20) 179.2(2)C(22)-N(4)-C(19)-C(20) 57.3(3)C(21)-O(2)-C(20)-C(19) 56.8(3)N(4)-C(19)-C(20)-O(2) -57.0(3)C(20)-O(2)-C(21)-C(22) -58.9(3)C(18)-N(4)-C(22)-C(21) 178.7(2)C(19)-N(4)-C(22)-C(21) -58.5(3)O(2)-C(21)-C(22)-N(4) 60.1(3)

_____________________________________________________________________

Table 2.6bHydrogen coordinates (× 104) and isotropicdisplacement parameters (Å2×103) of A2.

________________________________________________________________

Atom x y z U(eq)________________________________________________________________

H(2) 13199 450 685 28H(3) 10136 610 1451 28H(5) 8124 3946 24 27H(6) 11197 3846 -687 27H(11A) -317 2154 3948 29H(11B) -1181 2324 3006 29H(13) -995 4062 5019 28H(14) -3030 6114 5584 32H(16) -5254 6610 3183 35H(17) -3197 4534 2610 30H(18A) 5957 -408 2070 27H(18B) 7799 -388 1356 27H(19A) 5991 -609 3708 29H(19B) 6141 850 3720 29H(20A) 8870 131 4421 33H(20B) 7223 -309 5055 33H(21A) 11196 -2966 3386 39H(21B) 11268 -1487 3377 39H(22A) 10088 -1917 2036 34H(22B) 8419 -2304 2698 34H(23A) 14229 3185 -1523 50H(23B) 16197 2816 -1166 50H(23C) 14398 3829 -577 50

_______________________________________________________________


88

Table 2.7bMean planes through various groups of atoms and deviations (Å) from the plane, in A2.



1 -0.396(9) -0.524(1) -0.753(7) -5.013(8)C1*C2*C3*C4*C5*C6*

-0.0067(3)0.0135(3)-0.0092(3)-0.0013(3)0.0079(3)-0.0039(3)

2 -0.513(4) -0.269(6) -0.814(4) -5.286(2) C10* N1*

N2*C8*C7*N3*

C9* S1*

-0.0099(3)-0.0092(2)0.0106(2)0.0104(3)

-0.0075(3)-0.0099(2)0.0064(3)0.0008(7)

3 0.792(7) 0.447(1) -0.415(7) 0.208(4)C12*C13*C14*C15*C16*

C17*

-0.0056(3)0.0031(3)0.0031(3)

-0.0060(3)0.0032(3)0.0031(3)

4 0.832(7) 0.552(2) -0.037(6) 4.957(7)C19*C20*

O2*C21*C22*

N1*

-0.2718(3)0.2726(3)

-0.1227(2)0.3002(3)

-0.2843(3)0.1604(2)


Plane1 Plane2 Angle

Imidazothiadiazole ring Fluorobenzyl ring 79.21(2)°

Imidazothiadiazole ring Methoxyphenyl ring 17.45(3)°

Imidazothiadiazole ring Morpholinomethyl ring 85.58(5)°


89

Table 2.8bNonbonded interactions and possible hydrogen bonds in A2 (Å, °)


D–H...A D–H H...A D...A D–H...A

C3-H3...N4

C13-H13...O2i

C11-H11A O2i

C23-H23C...N3ii

C17–H17...N3iii

C19–H19B…F1iv

0.930(3)

0.930(3)

0.970(3)

0.960(3)

0.930(3)

0.970(3)

2.523(2)

2.566(2)

2.664(2)

2.871(2)

2.584(3)

2.666(2)

3.379(4)

3.407(3)

3.525(4)

3.471(4)

3.457(4)

3.517(4)

153

150

148

121

156

146

Symmetry code: (0) x, y, z (i) -x+1,-y,-z+1 (ii)-x+2,-y+1,-z (iii) x-1,+y,+z (iv) x+1,+y-1,+z

Chapter2 Imidazothiadiazoles

90

2.4. Crystal and molecular structure of 2-(4-fluorobenzyl)-6-phenyl-imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (A3)

Fig: 2.1c

2.4.1. Introduction

The title compound A3 (C1H12FN3OS), is one of the imidazo[2,1-b][1,3,4]thiadiazole

derivatives with pharmacophoric substituent have promising biological and

pharmacological activities. These fluorinated drugs possess metabolically non-

degradable properties leading to increase in lipid solubility, which will further

enhance the rate of absorption and transport of drug in vivo. Additionally, it is an

intermediate required for the synthesis of thiazolidine-2,4-dione derivative, which is

an expected antidiabetic agent. In view of the above facts and in continuation of our

search for various biologically active molecules, we attempted the synthesis and

structure analysis of the title compound.


The synthetic pathway used for the synthesis of compound A3 is outlined in Scheme

2C.


91

S

NN

NH2

F

Br

O

S

N N

N

F

S

N N

N

F CHO

+ i. Dry ethanol,

ii. Na2CO3

DMF/POCl3

1 23

4

A3

Scheme 2C

The title compound was prepared in two stages as shown in Scheme 2C. The reaction

of 2-amino-5-(4-Fluoro-benzyl)-1,3,4-thiadiazole [74] (1) and phenacyl bromide (2)

in boiling ethanol afforded the 2-(4-Fluoro-benzyl)-6-phenyl-imidazo[2,1-

b][1,3,4]thiadiazole (3) as hydrobromide salt, which was neutralized by sodium

carbonate solution to get the free base. It was subjected to Vilsmeier-Haack reaction

to yield 2-(4-Fluoro-benzyl)-6-phenyl-imidazo[2,1-b][1,3,4]thiadiazole-5-

carbaldehyde(4). The structure of the synthesized compound was established by

analytical and spectral data and confirmed by x-ray crystal structure analysis.

Preparation of 2-(4-Fluoro-benzyl)-6-phenyl-imidazo [2, 1- b] [1,3,4]thiadiazole carbaldehyde (A3):

Vilsmeier Haack reagent was prepared by adding phosphorous oxychloride

(3mL) in dimethylformamide (20mL) at 0oC with stirring. At the same temperature 2-

(4-Fluorobenzyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazole (3) (2.5g, 0.008mol) was

added to the reagent and stirred at 0-5oC for 30 minutes. The mixture was further

stirred for 2 hrs at room temperature and then at 60oC for additional 2 hrs. The

reaction mixture was cooled in ice water bath and quenched with 5mL water. The

reaction mixture was basified with aq. sodium carbonate (10%) solution with cooling


92

and further stirred at 80-90oC for 2 hrs. After cooling, the mixture was diluted with

water, extracted with chloroform (30mLx3). The combined extracts were washed with

water (100mLx3), dried over anhydrous sodium sulphate. Solvent was removed under

vacuum and the solid obtained A3 was recrystallized from chloroform to afford

yellow crystals in excellent yields.


The X-ray diffraction data were collected on a Bruker Smart CCD Area Detector System.

Intensity data were collected up to a maximum of 28.37 ° for the compound in the –

scan mode. The data were reduced using SAINTPLUS [57]. A total of 10140 reflections

were collected, resulting in 3876 independent reflections of which the number of

reflections satisfying I I) criteria were 2017. These were treated as observed. The

structure was solved by direct methods and difference Fourier synthesis using

SHELXS97 [58]. The positions of all non-hydrogen atoms were included in the full-

matrix least-square refinement using SHELXL97 [58]. Anisotropic refinement using full-

matrix least-square procedures was carried out for a few cycles until convergence was

reached. Then the hydrogen atoms were fixed geometrically. The R factor after final

convergence was 0.0559 and the maximum and minimum values of residual electron

density were 0.307 and –0.215 eÅ-3. Molecular diagrams were generated using ORTEP

[59] and the packing diagrams were generated using CAMERON [60]. The mean plane

calculation was done using the program PARST [61].


Figure 3.1a shows the chemical diagram of the compound studied. Table 3.1c

summarizes the crystal data, intensity data collection and refinement details for the

compound A3. The atomic coordinates of the nonhydrogen atoms with their

equivalent temperature factors for the compound are presented in Table 3.2c

anisotropic displacement parameters are given in Table 3.3c. The corresponding bond

lengths and angles are given in Tables 3.4c. The torsion angles for the nonhydrogen

atoms are listed in Table 3.5c. Table 3.6c shows the atomic coordinates and isotropic

temperature factors for the hydrogen atoms. The least-squares planes calculated using

the programs PARST [61] are tabulated in Table 3.7c. The intermolecular hydrogen

bonds are listed in Table 3.8c.


93

Fig: 2.2c



The title compound crystallizes in monoclinic space group P21/n. The

imidazothiadiazole and aryl ring are planar with a dihedral angle of 0.942(3)° between

them. Fluorobenzyl ring is inclined at an angle of 74° degree to these

imidazothiadiazole and aryl ring systems. The carbaldehyde group is coplanar with

imidazothiadiazole ring and cis to phenyl ring while the fluoro group is coplanar with

the benzyl ring. The carbonyl group

has a cis orientation with respect to the C5=C6 double bond which leads to strong

intramolecular hydrogen bond. The C-N bond lengths in the imidazole ring are longer

than that of a typical C=N bond but shorter than that of a C-N bond indicating

electron delocalization in the ring. The thiadiazole moiety displays differences in the

bond lengths of the pairs of bonds C3-N2/C6-N1and S1-C2/S1-C3 due to the fused

imidazole ring as well as due to the different groups that are attached on either sides

of the imidazothiadiazole ring system. The difference in bond lengths S1-C3

[1.720(3) Å] and S1-C2 [1.757(3) Å] indicates that the resonance effect caused by the

imidazole ring is stronger than that caused by the thiadiazole ring. The imidazole and

thiadiazole parts show diffe

the groups attached to them. This is evident from the C-N bond length similarities in

imidazole ring (having values intermediate between those of single and double bonds)


94

as against the C-S bond length differences in thiadiazole ring. As a result, the

imidazole part of this imidazothiadiazole system is more resonance stabilized.

Additionally, the imidazothiadiazole entity is generally planar and rigid. The

molecular structure is primarily stabilised by strong intramolecular C8-H8…O1

hydrogen bond [C8-H8 = 0.954(1)Å, H8…O1 = 2.127(1)Å, C8…O1 = 3.016(4)Å and

the angle C8-H8…O1 = 154(2)°] leading to the formation of a pseudo-seven-

membered hydrogen bonded pattern with graph set S(7), thus locking the molecular

conformation and eliminating conformational flexibility.


The crystal structure is stabilized by intermolecular interactions into three

dimensional framework structure by the combination of C-H…N, C-H…O and C-

H…F. Hydrogen bonds with C-H as donor play a significant role, as functional and

structural, contributing to the overall stability of the molecular packing. The

framework is composed of two different C-H…N interactions, the first is from C14 to

its neighbour N1 linking the molecule in terms of zig-zag chain like structure and the

second C-H…N interaction between C4 and N3 form head-to-head dimers

corresponding to graph set notation of R22(10), (Fig 2.3c).

Fig. 2.3c: Crystal structure of A3 viewed along ‘b’ axis. Dotted lines indicate

intermolecular C-H…N interaction generating head to head dimers


95

There are two different C-H…O interactions, in the former the molecules are linked

by paired C-H…O hydrogen bonds into centrosymmetric dimers corresponding to

graph set notation R22(18) and the latter generate bifurcated bonds from two donors,

C1 and C14 to the same acceptor, O1 along ‘b’ axis (Fig 2.4c).

Fig. 2.4c

Crystal structure of A3 viewed along ‘b’ axis. Dotted lines indicate intermolecular C-H…O interaction generating bifurcated bonds.

The C-H…F interactions creates self assembly in terms of two dimensional sheet like

structure along crystallographic ‘b’ axis (Fig 2.5c).

Fig. 2.5c

Crystal structure of 4 representing two dimensional sheets like structureDotted lines indicate intermolecular C-H…F interactions.


96

The dependence of the strength of the C-H…X interaction on C-H group acidity [65,

66] meant that the selected compounds should have as large a number of acidic C-H

groups as possible [75]. Thus, we were led to a conclusion on the basis of CSD and

computational studies, that the C-F group does not favor the formation of F… F

contacts as do the C-Cl, C-Br, and C-I groups [76]. This difference between F and the

other halogens has been noted in several other studies [77]. The presence of the fluoro

substituent on the benzene ring enhances the acidity of the C-H groups. There are no

aromatic - stacking interactions. The supramolecular aggregation in this structure is

thus limited to the C-H…N, C-H…O and C-H…F intermolecular interactions giving

overall stability to the structure.


97

Table 2.1cSummary of crystal data, intensity data collection and refinement of A3

compound

Crystal data C18H12FN3OS

Mr = 336.36Monoclinic, P21/n a = 7.419(3)Åb = 8.287(3)Åc = 25.734(10)Å

= 91.686(8)°

V = 1581.6(10)Å3

Z = 4


and scansAbsorption correction: none10140 measured reflections

3876 independent reflections


R[F2 2)]= 0.0559wR(F2) = 0.1674S = 1.003876 reflections

241 parameters H atoms treated by a mixture of independent and constrained

refinement

Dx = 1.430Mgm-3

= 2.58 - 28.37°

µ = 0.225mm1

T = 293 (2) K Prism, white0.4 × 0.35 × 0.3 mm

2017Rint = 0.0476

max = 28.35°h = -k = -10l = -

w = 1/[\s2(Fo2)+(0.0782P)2

+0.0000P]where P=(Fo2+2Fc2)/3'

max = 0.001

max = 0.307 e Å–3

min = -0.215 e Å–3


CAMERON Watkin et al., 1993); WinGX (Farrugia, 1999)

Data deposition



98

Table 2.2cAtomic coordinates ( × 104) and equivalent isotropic


Atom x y z U(eq) ________________________________________________________________ C(1) 5750(4) 4545(4) 1606(1) 57(1) C(2) 6197(3) 3266(3) 1223(1) 52(1)

C(3) 7185(3) 851(3) 787(1) 49(1) C(4) 6226(4) 2748(3) -431(1) 63(1) C(5) 6781(3) 1627(3) -31(1) 45(1) C(6) 7450(3) 48(3) 6(1) 46(1) C(7) 7896(3) -1143(3) -394(1) 48(1) C(8) 7708(4) -838(4) -925(1) 58(1) C(9) 8149(4) -2015(4) -1282(1) 67(1) C(10) 8778(4) -3488(4) -1119(1) 67(1) C(11) 8977(4) -3803(4) -603(1) 71(1) C(12) 8544(4) -2651(3) -240(1) 62(1) C(13) 7425(3) 5441(3) 1791(1) 51(1) C(14) 8030(4) 6742(3) 1512(1) 64(1) C(15) 9600(5) 7530(4) 1656(2) 80(1) C(16) 10560(4) 6987(5) 2081(2) 83(1) C(17) 10021(5) 5705(5) 2371(1) 80(1) C(18) 8431(4) 4940(4) 2224(1) 67(1) N(1) 7683(3) -419(2) 520(1) 51(1) N(2) 6640(3) 2099(2) 485(1) 46(1) N(3) 6077(3) 3486(2) 721(1) 51(1) O(1) 6290(3) 2571(2) -898(1) 80(1) S(1) 6995(1) 1370(1) 1431(1) 59(1) F(1) 12118(3) 7741(3) 2228(1) 132(1) ________________________________________________________________



99

Table 2.3cAnisotropic displacement parameters (Å2×103) of A3


_______________________________________________________________________

Atom U11 U22 U33 U23 U13 U12 _______________________________________________________________________

C(1) 54(2) 60(2) 56(2) -2(1) 6(1) 2(1) C(2) 48(1) 52(2) 56(2) 2(1) 2(1) -1(1) C(3) 45(1) 50(2) 51(2) 10(1) -3(1) -2(1) C(4) 78(2) 52(2) 58(2) 6(1) 2(2) 7(1) C(5) 42(1) 49(2) 46(2) 4(1) 1(1) -5(1) C(6) 39(1) 48(1) 50(2) 2(1) -1(1) -5(1)

C(7) 38(1) 51(2) 54(2) 0(1) -2(1) -5(1) C(8) 55(2) 57(2) 61(2) 1(1) 1(1) -4(1) C(9) 64(2) 76(2) 62(2) -12(2) -1(1) -2(2) C(10) 56(2) 73(2) 73(2) -19(2) 0(2) 7(1) C(11) 71(2) 61(2) 80(2) -4(2) -3(2) 15(2) C(12) 63(2) 60(2) 60(2) 0(2) -6(2) 8(1) C(13) 60(2) 49(2) 45(2) -4(1) 6(1) 7(1) C(14) 73(2) 54(2) 64(2) 4(1) 2(2) 4(1) C(15) 83(2) 60(2) 95(3) -5(2) 9(2) -12(2) C(16) 68(2) 92(3) 89(3) -37(2) 1(2) -15(2) C(17) 81(2) 103(3) 55(2) -19(2) -13(2) 6(2) C(18) 83(2) 75(2) 42(2) 1(1) 4(1) -2(2) N(1) 54(1) 47(1) 53(1) 1(1) -1(1) 1(1) N(2) 49(1) 40(1) 49(1) 4(1) 1(1) 1(1) N(3) 51(1) 45(1) 56(1) -1(1) 0(1) 1(1) O(1) 114(2) 71(1) 54(1) 12(1) 0(1) 23(1) S(1) 70(1) 59(1) 49(1) 5(1) -1(1) 5(1) F(1) 98(2) 150(2) 148(2) -49(2) -14(1) -45(2)

_______________________________________________________________________


100

Table 2.4c Bond lengths [Å] and angles [°] for non H-atoms of A3

with esds in parenthesis. _____________________________________________________________

C(1)-C(2) 1.491(4)C(1)-C(13) 1.513(4)C(2)-N(3) 1.305(3)C(2)-S(1) 1.757(3)C(3)-N(1) 1.317(3)C(3)-N(2) 1.349(3)C(3)-S(1) 1.720(3)C(4)-O(1) 1.214(3)C(4)-C(5) 1.438(4)C(5)-N(2) 1.391(3)C(5)-C(6) 1.401(3)C(6)-N(1) 1.385(3)C(6)-C(7) 1.471(3)C(7)-C(8) 1.392(4)C(7)-C(12) 1.393(4)C(8)-C(9) 1.386(4)C(9)-C(10) 1.369(4)C(10)-C(11) 1.357(4)C(11)-C(12) 1.381(4)C(13)-C(14) 1.377(4)C(13)-C(18) 1.386(3)C(14)-C(15) 1.376(4)C(15)-C(16) 1.365(5)C(16)-F(1) 1.358(3)C(16)-C(17) 1.365(5)C(17)-C(18) 1.382(4)N(2)-N(3) 1.371(3)

C(2)-C(1)-C(13) 111.1(2)N(3)-C(2)-C(1) 123.0(2)N(3)-C(2)-S(1) 116.00(19)C(1)-C(2)-S(1) 120.9(2)N(1)-C(3)-N(2) 113.3(2)N(1)-C(3)-S(1) 137.3(2)N(2)-C(3)-S(1) 109.42(19)O(1)-C(4)-C(5) 127.7(3)N(2)-C(5)-C(6) 103.57(19)N(2)-C(5)-C(4) 118.2(2)C(6)-C(5)-C(4) 138.2(2)N(1)-C(6)-C(5) 111.1(2)N(1)-C(6)-C(7) 117.2(2)C(5)-C(6)-C(7) 131.7(2)C(8)-C(7)-C(12) 117.8(3)C(8)-C(7)-C(6) 123.1(2)C(12)-C(7)-C(6) 119.0(2)C(9)-C(8)-C(7) 120.3(3)C(10)-C(9)-C(8) 120.6(3)C(11)-C(10)-C(9) 119.9(3)C(10)-C(11)-C(12) 120.6(3)

C(11)-C(12)-C(7) 120.8(3)C(14)-C(13)-C(18) 118.5(3)C(14)-C(13)-C(1) 119.8(2)C(18)-C(13)-C(1) 121.6(3)

_____________________________________________________________


101

Table 2.4c. (Contd.)_______________________________________________________

C(15)-C(14)-C(13) 121.2(3)C(16)-C(15)-C(14) 118.4(3)F(1)-C(16)-C(17) 117.9(4)F(1)-C(16)-C(15) 119.4(4)C(17)-C(16)-C(15) 122.7(3)C(16)-C(17)-C(18) 117.9(3)C(17)-C(18)-C(13) 121.2(3)C(3)-N(1)-C(6) 104.3(2)C(3)-N(2)-N(3) 118.5(2)C(3)-N(2)-C(5) 107.8(2)N(3)-N(2)-C(5) 133.71(19)C(2)-N(3)-N(2) 108.0(2)

C(3)-S(1)-C(2) 88.11(12) _____________________________________________________________

Table 2.5c

Torsion angles [°] for non H-atoms of V1 with esds in parenthesis________________________________________________________________

C(13)-C(1)-C(2)-N(3) -95.7(3)C(13)-C(1)-C(2)-S(1) 82.2(3)O(1)-C(4)-C(5)-N(2) 178.0(3)O(1)-C(4)-C(5)-C(6) -3.8(5)N(2)-C(5)-C(6)-N(1) 0.6(2)C(4)-C(5)-C(6)-N(1) -177.7(3)N(2)-C(5)-C(6)-C(7) 179.6(2)C(4)-C(5)-C(6)-C(7) 1.3(5)N(1)-C(6)-C(7)-C(8) 179.3(2)C(5)-C(6)-C(7)-C(8) 0.4(4)N(1)-C(6)-C(7)-C(12) -0.8(3)C(5)-C(6)-C(7)-C(12) -179.8(2)C(12)-C(7)-C(8)-C(9) 0.3(4)C(6)-C(7)-C(8)-C(9) -179.8(2)C(7)-C(8)-C(9)-C(10) -0.1(4)C(8)-C(9)-C(10)-C(11) -0.1(4)C(9)-C(10)-C(11)-C(12) 0.3(5)C(10)-C(11)-C(12)-C(7) -0.1(5)C(8)-C(7)-C(12)-C(11) -0.2(4)C(6)-C(7)-C(12)-C(11) 179.9(3)C(2)-C(1)-C(13)-C(14) 86.5(3)C(2)-C(1)-C(13)-C(18) -90.3(3)C(18)-C(13)-C(14)-C(15) 0.3(4)C(1)-C(13)-C(14)-C(15) -176.6(3)C(13)-C(14)-C(15)-C(16) 0.3(5)C(14)-C(15)-C(16)-F(1) 179.6(3)C(14)-C(15)-C(16)-C(17) -0.4(5)F(1)-C(16)-C(17)-C(18) 179.7(3)C(15)-C(16)-C(17)-C(18) -0.2(5)C(16)-C(17)-C(18)-C(13) 0.9(4)C(14)-C(13)-C(18)-C(17) -0.9(4)C(1)-C(13)-C(18)-C(17) 175.9(3)N(2)-C(3)-N(1)-C(6) 0.3(3)S(1)-C(3)-N(1)-C(6) 179.0(2)C(5)-C(6)-N(1)-C(3) -0.6(3)C(7)-C(6)-N(1)-C(3) -179.76(19)

________________________________________________________________


102

Table 2.5c. (Contd.)_________________________________________________________

N(1)-C(3)-N(2)-N(3) 179.57(19)S(1)-C(3)-N(2)-N(3) 0.6(2)N(1)-C(3)-N(2)-C(5) 0.1(3)S(1)-C(3)-N(2)-C(5) -178.97(15)C(6)-C(5)-N(2)-C(3) -0.4(2)C(4)-C(5)-N(2)-C(3) 178.4(2)C(6)-C(5)-N(2)-N(3) -179.8(2)C(4)-C(5)-N(2)-N(3) -1.1(4)C(1)-C(2)-N(3)-N(2) 178.0(2)S(1)-C(2)-N(3)-N(2) 0.0(3)C(3)-N(2)-N(3)-C(2) -0.4(3)C(5)-N(2)-N(3)-C(2) 179.0(2)N(1)-C(3)-S(1)-C(2) -179.1(3)N(2)-C(3)-S(1)-C(2) -0.42(17)N(3)-C(2)-S(1)-C(3) 0.3(2)C(1)-C(2)-S(1)-C(3) -177.8(2)

________________________________________________________________

Table 2.6cHydrogen coordinates (× 104) and isotropicdisplacement parameters (Å2×103) of V1.

________________________________________________________________

Atom x y z U(eq) ________________________________________________________________

H(1A) 4780(30) 5290(30) 1448(9) 64(8) H(1B) 5120(30) 4050(30) 1899(10) 50(7) H(4) 5762 3725 -318 75 H(8) 7230(40) 190(40) -1029(11) 84(10) H(9) 8017 -1801 -1636 81 H(10) 9068 -4272 -1362 81 H(11) 9410(40) -4740(40) -469(11) 81(9) H(12) 8730(30) -2880(30) 110(11) 54(7) H(14) 7365 7095 1222 76 H(15) 10090(50) 8480(40) 1474(13) 101(11) H(17) 10702 5356 2659 96 H(18) 8030 4073 2418 80 ________________________________________________________________


103

Table 2.7cMean planes through various groups of atoms and deviations (Å) from the plane, in V1.



1 0.937(4) 0.347(9) -0.0061(2) 5.198(4)C7*C8*C9*C10*C11*C12*

-0.0014(2)0.0017(2)0.0001(3)

-0.0015(3)0.0014(3)0.0008(3)

2 -0.937(2) -0.347(6) -0.010(4) -5.197(2) C2* N3*

N2*C5*C6*N1*C3*S1*

0.0002(2)-0.0025(2)-0.0043(2)0.0101(2)0.0020(2)-0.0026(2)-0.0104(2)-0.0010(1)

3 0.531(2) -0.618(4) -0.578(7) -2.604(2) C13* C14*

C15* C16* C17* C18*

0.0027(2)0.001(3)

-0.0040(3)0.0018(3)0.0038(3)

-0.0052(3)


Plane1 Plane2 Angle

Imidazothiadiazole ring Aryl ring 0.942(3)°



104

Table 2.8cNonbonded interactions and possible hydrogen bonds in A3 (Å, °)


D—H· · ·A D—H H· · ·A D· · ·A D—H· · ·A

C8-H8…O1

C14-H14...N1i

C4-H4...N3ii

C14-H14...O1iii

C1-H1A...O1iii

C17-H17...F1iv

0.954(1)

0.930 (3)

1.023(5)

0.930(3)

1.023(5)

0.930(3)

2.127{1)

2.755(2)

2.389(5)

2.827(2)

2.827(2)

2.715(2)

3.016{4)

3.477(4)

3.340(4)

3.577 (4)

3.340(4)

3.388(4)

154(2)

135 (0)

154(2)

138 (0)

154(2)

129(0)

Symmetry code: (i) x,+y+1,+z ; (ii) -x+1,-y+1,-z; (iii) -x+1,-y+1,-z; (iv) -x+1/2+2,+y-1/2,-z+1/2


105

2.5. Crystal and molecular structure of 2-(4-Fluorobenzyl)-6-(4-

methoxyphenyl)Imidazo[2,1-b][1,3,4]thiadiazole (A4)

Fig. 2.1d

2.5.1. Introduction

The title compound A4 (C14H13N3O2), being an imidazo[2,1-b][1,3,4]thiadiazole

derivative, has significant pharmacological prospects. It belongs to the class of 5-5

heterocyclic ring system with more than two heteroatoms. This compound was chosen

for X-ray crystallographic study with the intention of correlating its structure to its

activity.



2D.

S

NN

NH2

F

Br

O

MeO

S

N N

N

FOMe

+

12

i. dry ethanol,reflux

ii. aq.Na2CO3

A4

Scheme 2D


and p-methoxy phenacyl bromide (0.01mol) was refluxed in dry ethanol for 12 hrs.

The excess of solvent was distilled off and the solid hydrobromide salt that separated

was collected by filtration, suspended in water and neutralized by aqueous sodium

carbonate solution to get free base (2). It was filtered, washed with water, dried and

recrystallized from ethanol and dioxane mixture to afford white needles. Yield 65%

(3.78g) A4.


106


The X-ray diffraction data, for the compound A4 was collected on a Bruker Smart CCD

Area Detector System at I.I.Sc., Bangalore, using MoK (0.71073Å) radiation for the

crystal. The data were reduced using SAINTPLUS [57]. The structure was solved by

direct methods using SHELXS97 [58] and difference Fourier synthesis using

SHELXL97 [58]. The positions and anisotropic displacement parameters of all non-

hydrogen atoms were included in the full-matrix least-square refinement using

SHELXL97 [58] and the procedures were carried out for a few cycles until convergence

was reached. The H atoms were placed at calculated positions in the riding model

approximation (C—H 0.93Å); their temperature factors were set to 1.2 times those of

the equivalent isotropic temperature factors of the parent atoms. All other non-H atoms

were refined anisotropically. Molecular diagrams were generated using ORTEP [59].




were 1782. These were treated as observed. The R factor after final convergence was

0.0618 and the maximum and minimum values of residual electron density were

0.232 and – 0.247 eÅ-3.


Figure 2.1d shows the chemical diagram of the compound A4. Table 2.1d summarizes



factors for the compound are presented in Table 2.2d. Anisotropic displacement

parameters are given in Table 2.3d. The corresponding bond lengths and angles are

given in Tables 2.4d. The torsion angles for the nonhydrogen atoms are listed in Table

2.5d. Table 2.6d shows the atomic coordinates and isotropic temperature factors for


[61] are tabulated in Table 2.7d. The intermolecular hydrogen bonds are listed in

Table 2.8d.


107

Fig: 2.2d



Molecule (Fig.2.2d) crystallizes in monoclinic space group P21/n. The imidazo-

thiadiazole and methoxyphenyl rings are coplanar with only 7.9° between them.

Fluorobenzyl ring is inclined at an angle of 68.8° to these two ring systems. The

methoxy group is cis to imidazo-thiadiazole and benzene ring.

The difference in bond lengths S1-C1 [1.7210(17) Å] and S1-C2 [1.7627(17)

Å] indicates that the resonance effect caused by the imidazole ring is stronger than

that caused by the thiadiazole ring. The C-N bond lengths in the imidazole ring are

longer than that of a typical C=N bond but shorter than that of a C-N bond indicating

electron delocalisation in the ring. The thiadiazole moiety displays differences in the

bond lengths of the pairs of bonds C1-N1/C2-N2 and S1-C1/S1-C2 due to the fused

imidazole ring as well as the different groups attached on either sides of the

imidazothiadiazole ring system. The presence of fluorine atoms attached to the

aromatic ring increases the acidity of the aromatic hydrogen atoms as is generally

observed with aromatic compounds [73] and the strength of any C-H...X interaction

(X =halogen) depends on C-H group acidity. Regarding the location of the F atom, the

flourobenzyl group is attached to the thiadiazole part of imidazo-thiadiazole system.

In the molecule, an intramolecular interaction of C11-H11…N1 hydrogen bond [C11-

H11 = 0.930(3)Å, H11…N1 = 2.572{2)Å, C11…N1 = 2.899{4)Å and the angle C11-

H11…N1 = 101.12(9)°] forms a pseudo-five-membered hydrogen bonded pattern


108

with graph set S(5), thus locking the molecular conformation and eliminating

conformational flexibility.


In the crystal structure, there are C-H…N interactions (Fig. 2.3d) (C11 -H11B ...N1)

linking the molecules through centrosymmetric dimers corresponding to graph set

[62] R22(12), along crystallographic ‘c’ axis. Additionally there are F…F short

contacts (3.081Å) (Fig 2.4d), providing cohesion. The molecular packing is further

stabilized by - stacking interactions between the benzene and imidazothiadiazole

ring systems [79]

(Fig.2.5d). The shortest centroid–centroid distance is 3.502Å [for Cg…Cg1 symmetry

code: ½–x, -½+y, ½-z; Cg1 is the centroid of the C3/N1/C6/C4/N3 ring].

Fig. 2.3d: The dimers in compound A4 formed by C-H…N interactions.


109

Fig. 2.4dThe molecular packing in A4 stabilized by F…F short contacts

Fig. 2.5d

- A4


110

Table 2.1dSummary of crystal data, intensity data collection and refinement of A4

compound

Crystal data C18H14FN3OS

Mr = 339.38Monoclinic, P21/n

a = 11.119(7) Å . b = 5.667(4) Å c = 25.385(5) Å. = 91.185(13) °. V = 1599.1(14) Å3

Z = 4






refinement

Dx = 1.410 Mgm-3

= 3.00 - 28.34°µ = 0.223 mm-1

T = 293 (2) K Prism, white0.4 × 0.35 × 0.3 mm

Rint = 0.0623

max = 28.34°h = -k = -l = -

w = 1/[\s2(Fo2)+(0.0923P)2

+0.0000P]where P = (Fo2 + 2Fc

2)/3

max = 0.001

max = 0.232 e Å–3

min = -0.247 e Å–3



Data deposition



111

Table 2.2dAtomic coordinates (× 104) and equivalent isotropic


Atom x y z U(eq) ________________________________________________________________

C(1) 1462(3) 8531(6) 3919(1) 81(1) C(2) 1497(3) 6537(6) 3605(1) 85(1) C(3) 2383(3) 6315(5) 3237(1) 80(1) C(4) 3264(2) 8025(4) 3168(1) 65(1) C(5) 3191(3) 10011(5) 3485(1) 79(1) C(6) 2310(3) 10245(5) 3855(1) 87(1) C(7) 4215(2) 7768(4) 2782(1) 65(1) C(8) 4497(3) 5842(5) 2484(1) 78(1) C(9) 5729(3) 8787(5) 2329(1) 71(1) C(10) 7001(3) 6854(5) 1694(1) 78(1) C(11) 7969(3) 6185(6) 1327(1) 92(1) C(12) 8272(3) 8051(5) 927(1) 76(1) C(13) 7698(3) 8066(5) 434(1) 84(1) C(14) 7966(3) 9773(6) 69(1) 89(1) C(15) 8796(3) 11471(6) 197(1) 86(1) C(16) 9365(3) 11520(6) 673(2) 94(1) C(17) 9108(3) 9809(6) 1038(1) 89(1) C(18) -269(4) 7229(7) 4390(1) 123(1) S(1) 6960(1) 9682(1) 1980(1) 90(1) N(1) 5001(2) 9620(4) 2684(1) 73(1) N(2) 6167(3) 5419(5) 1837(1) 87(1) N(3) 5460(2) 6519(4) 2195(1) 73(1) F(1) 9054(2) 13141(4) -165(1) 124(1) O(1) 645(2) 8936(5) 4306(1) 106(1) ________________________________________________________________



112

Table 2.3dAnisotropic displacement parameters (Å2×103) of A4


_______________________________________________________________________

Atom U11 U22 U33 U23 U13 U12 _______________________________________________________________________

C(1) 80(2) 87(2) 75(2) 7(2) -9(2) 5(2) C(2) 86(2) 79(2) 90(2) 12(2) -8(2) -16(2) C(3) 92(2) 63(2) 83(2) -4(1) -16(2) -6(2) C(4) 73(2) 54(2) 67(1) 2(1) -19(1) 4(1) C(5) 85(2) 60(2) 92(2) -11(1) 2(2) -7(1) C(6) 97(2) 75(2) 89(2) -15(2) 1(2) -3(2) C(7) 73(2) 52(1) 68(2) -3(1) -19(1) 6(1) C(8) 94(2) 54(2) 85(2) -12(1) -6(2) -2(2) C(9) 86(2) 54(1) 73(2) -8(1) -9(1) 9(1) C(10) 96(2) 66(2) 72(2) -6(1) -8(2) 25(2) C(11) 104(2) 86(2) 87(2) -6(2) 2(2) 32(2) C(12) 77(2) 79(2) 72(2) -17(2) -3(1) 22(2) C(13) 82(2) 81(2) 89(2) -13(2) -9(2) 2(2) C(14) 85(2) 96(2) 86(2) -6(2) -11(2) 1(2) C(15) 87(2) 79(2) 93(2) -8(2) 12(2) 11(2) C(16) 84(2) 90(2) 108(2) -32(2) 2(2) 2(2) C(17) 81(2) 100(2) 85(2) -35(2) -16(2) 22(2) C(18) 102(3) 145(3) 123(3) 38(3) 11(2) -10(3) S(1) 107(1) 67(1) 97(1) -15(1) 19(1) 2(1) N(1) 85(2) 55(1) 79(1) -10(1) 0(1) 0(1) N(2) 111(2) 64(2) 85(2) -18(1) -2(2) 16(2) N(3) 92(2) 53(1) 75(1) -14(1) -9(1) 10(1) F(1) 133(2) 106(2) 134(2) 10(1) 23(1) -4(1) O(1) 101(2) 124(2) 94(1) 6(1) 15(1) -11(2) ____________________________________________________________________

Table 2.4dBond lengths [Å] and angles [°] for non H-atoms of A4

with esds in parenthesis. _____________________________________________________________

C(1)-C(6) 1.366(4)C(1)-C(2) 1.384(4)C(2)-C(3) 1.376(4)C(3)-C(4) 1.392(4)C(4)-C(5) 1.388(4)C(4)-C(7) 1.463(4)C(5)-C(6) 1.377(4)C(7)-C(8) 1.369(3)C(10)-C(11) 1.487(4)C(11)-C(12) 1.508(4)C(12)-C(17) 1.387(4)C(12)-C(13) 1.395(4)

________________________________________________________________


113

Table 2.4d. (Contd.)_______________________________________________________

C(13)-C(14) 1.375(4)C(14)-C(15) 1.367(4)C(15)-C(16) 1.352(4)C(16)-C(17) 1.375(5)S(1)-C(9) 1.723(3)S(1)-C(10) 1.760(3)N(1)-C(9) 1.312(3)N(1)-C(7) 1.391(3)N(2)-C(10) 1.291(4)N(2)-N(3) 1.365(3)N(3)-C(9) 1.361(3)N(3)-C(8) 1.365(4)F(1)-C(15) 1.355(4)O(1)-C(1) 1.371(4)O(1)-C(18) 1.422(4)

C(9)-N(1)-C(7) 104.5(2)C(10)-N(2)-N(3) 109.0(2)C(9)-N(3)-C(8) 107.6(2)C(9)-N(3)-N(2) 118.1(3)C(8)-N(3)-N(2) 134.2(2)C(1)-O(1)-C(18) 118.7(3)C(6)-C(1)-O(1) 115.9(3)C(6)-C(1)-C(2) 118.9(3)O(1)-C(1)-C(2) 125.2(3)C(3)-C(2)-C(1) 119.6(3)C(2)-C(3)-C(4) 122.5(3)C(5)-C(4)-C(3) 116.2(3)C(5)-C(4)-C(7) 121.4(3)C(3)-C(4)-C(7) 122.4(2)C(6)-C(5)-C(4) 121.7(3)C(1)-C(6)-C(5) 121.0(3)C(8)-C(7)-N(1) 110.5(3)C(8)-C(7)-C(4) 128.8(3)N(1)-C(7)-C(4) 120.6(2)N(3)-C(8)-C(7) 105.3(2)N(1)-C(9)-N(3) 112.1(3)N(1)-C(9)-S(1) 139.1(2)N(3)-C(9)-S(1) 108.8(2)N(2)-C(10)-C(11) 123.3(3)N(2)-C(10)-S(1) 115.7(2)C(11)-C(10)-S(1) 121.0(3)C(10)-C(11)-C(12) 114.7(2)C(17)-C(12)-C(13) 118.0(3)C(17)-C(12)-C(11) 121.7(3)C(13)-C(12)-C(11) 120.3(3)C(14)-C(13)-C(12) 120.4(3)C(15)-C(14)-C(13) 119.3(3)C(16)-C(15)-F(1) 119.3(3)C(16)-C(15)-C(14) 121.9(3)F(1)-C(15)-C(14) 118.8(3)C(15)-C(16)-C(17) 119.1(3)C(16)-C(17)-C(12) 121.2(3)C(9)-S(1)-C(10) 88.36(15)

_____________________________________________________________


114

Table 2.5dTorsion angles [°] for non H-atoms of A4 with esds in parenthesis

________________________________________________________________

C(10)-N(2)-N(3)-C(9) 0.4(3)C(10)-N(2)-N(3)-C(8) -177.5(3)C(18)-O(1)-C(1)-C(6) 179.4(3)C(18)-O(1)-C(1)-C(2) -1.7(4)C(6)-C(1)-C(2)-C(3) 0.3(4)O(1)-C(1)-C(2)-C(3) -178.5(3)C(1)-C(2)-C(3)-C(4) 0.3(4)C(2)-C(3)-C(4)-C(5) -1.1(4)C(2)-C(3)-C(4)-C(7) 179.1(2)C(3)-C(4)-C(5)-C(6) 1.2(4)C(7)-C(4)-C(5)-C(6) -178.9(2)O(1)-C(1)-C(6)-C(5) 178.8(3)C(2)-C(1)-C(6)-C(5) -0.2(5)C(4)-C(5)-C(6)-C(1) -0.6(5)C(9)-N(1)-C(7)-C(8) 0.5(3)C(9)-N(1)-C(7)-C(4) 179.3(2)C(5)-C(4)-C(7)-C(8) 171.9(3)C(3)-C(4)-C(7)-C(8) -8.3(4)C(5)-C(4)-C(7)-N(1) -6.8(3)C(3)-C(4)-C(7)-N(1) 173.1(2)C(9)-N(3)-C(8)-C(7) 0.4(3)N(2)-N(3)-C(8)-C(7) 178.5(3)N(1)-C(7)-C(8)-N(3) -0.6(3)C(4)-C(7)-C(8)-N(3) -179.3(2)C(7)-N(1)-C(9)-N(3) -0.2(3)C(7)-N(1)-C(9)-S(1) -178.9(2)C(8)-N(3)-C(9)-N(1) -0.1(3)N(2)-N(3)-C(9)-N(1) -178.6(2)C(8)-N(3)-C(9)-S(1) 178.98(17)N(2)-N(3)-C(9)-S(1) 0.5(3)C(10)-S(1)-C(9)-N(1) 177.8(3)C(10)-S(1)-C(9)-N(3) -0.96(19)N(3)-N(2)-C(10)-C(11) 176.7(2)N(3)-N(2)-C(10)-S(1) -1.2(3)C(9)-S(1)-C(10)-N(2) 1.3(2)C(9)-S(1)-C(10)-C(11) -176.7(2)N(2)-C(10)-C(11)-C(12) 139.0(3)S(1)-C(10)-C(11)-C(12) -43.1(3)C(10)-C(11)-C(12)-C(17) 87.1(4)C(10)-C(11)-C(12)-C(13) -92.0(3)C(17)-C(12)-C(13)-C(14) 0.4(4)C(11)-C(12)-C(13)-C(14) 179.6(3)C(12)-C(13)-C(14)-C(15) -0.5(5)C(13)-C(14)-C(15)-C(16) 0.2(5)C(13)-C(14)-C(15)-F(1) 179.9(3)F(1)-C(15)-C(16)-C(17) -179.4(3)C(14)-C(15)-C(16)-C(17) 0.3(5)C(15)-C(16)-C(17)-C(12) -0.4(5)C(13)-C(12)-C(17)-C(16) 0.0(4)C(11)-C(12)-C(17)-C(16) -179.1(3)_______________________________________________________________


115

Table 2.6dHydrogen coordinates (× 104) and isotropic


Atom x y z U(eq) ________________________________________________________________ H(8) 925 5355 3642 102 H(7) 2393 4971 3027 96 H(11) 3752 11213 3448 95 H(10) 2292 11592 4064 105 H(4) 4114 4382 2479 93 H(1A) 7726 4762 1141 111 H(1B) 8690 5816 1532 111 H(13) 7130 6913 350 101 H(14) 7587 9772 -261 107 H(16) 9924 12696 752 113 H(17) 9502 9832 1365 107 H(18A) -780 7120 4081 185 H(18B) -740 7692 4685 185 H(18C) 94 5721 4459 185 ________________________________________________________________

Table 2.7dMean planes through various groups of atoms and deviations (Å) from the plane, in A4.



1 0.732(1) -0.578(1) -0.358(5) 3.222(6)C12*C13*C14*C15*C16*C17*

0.0011(3)-0.0030(3)0.0023(3)0.0005(3)-0.0027(3)0.0015(3)

2 -0.595(4) 0.325(7) -0.734(5) -6.450(5) C2* C3*

C4*C6*N1*N2*

N3* S1*

-0.0243(3)0.0097(2)-0.0016(3)-0.0065(2)-0.0062(2)0.0012(2)0.0146(2)0.0009(9)

3 -0.575(9) 0.449(1) -0.683(9) -5.434(4)C5*C7*C8*C9*C10*

C11*

-0.0055(2)0.0043(3)0.0017(3)

-0.0040(3)0.0000(3)0.0056(3)


116


Plane1 Plane2 Angle


Imidazothiadiazole ring Methoxyphenyl ring 8.03(3)°

Table 2.8dNonbonded interactions and possible hydrogen bonds in A4 (Å, °)


D–H...A D–H H...A D...A D–H...A

C11–H11B...N1 0.970(3) 2.532(2) 3.456(4) 159

Symmetry code: -x+1/2+1, +y-1/2, -z+1/2


117

2.6. Crystal and molecular structure of 2-(Fluorobenzyl)-6-(4-nitrophenyl) imidazo [2,1-b][1,3,4]thiadiazole (A5)

Fig: 2.1e.

2.6.1. Introduction

The title compound A5 (C17H11FN4O2S), is one of the series of Imidazo[2,1-b][1.3.4]

thiadiazole derivatives with pharmacophoric subsubstituents. 1,3,4-thiadiazoles are

known for their promising biological and pharmacological activities, possibly due to

the presence of the pharmacophoric isothioamide (S–C=N-) unit in the thiadiazole

nucleus. Its X-ray crystal structure investigation of this novel heterocyclic system

was undertaken with the intention that it will assist in pharmacological studies of

these compounds.


The title compound A5 was prepared as shown in the Scheme 2E. A mixture of 2-

amino-(4-fluorobenyl)-1,3,4-thiadiazole (1) (2.69, 0.013mol) and nitro phenacyl

bromide (2) (0.01mol) of equimolar quantities was refluxed in dry ethanol for 18 hrs.

The excess of solvent was distilled off and by filtration the solid hydrobromide salt

that separated was collected, suspended in water and neutralized by aqueous sodium


recrystallized from ethanol. It is well established that this reaction proceeds via the

intermediate iminothiadiazole which under reflux temperature spontaneously

undergoes dehydrocyclisation to form the desired fused -

haloaryl ketones were prepared by the bromination of the corresponding ketones.


118

Dry EtOH, 18hr

Na2CO3

1 2 3

A5

Scheme 2E


The X-ray diffraction data for the compound A5 was collected on a Bruker

Smart CCD Area Detector System, using MoK (0.71073Å) radiation for the crystal.

Intensity data were collected up to a maximum of 28.58° in the –

data were reduced using SAINTPLUS [57]. The structure was solved by direct

methods using SHELXS97 [58] and difference Fourier synthesis using SHELXL97

[58]. The positions and anisotropic displacement parameters of all non-hydrogen

atoms were included in the full-matrix least-square refinement using SHELXL97 [58]

and the procedure were carried out for a few cycles until convergence was reached. A

total of 9096 reflections were collected, resulting in 3701 [R(int) = 0.0847]


were 2733. These were treated as observed. The H atoms were placed at calculated

positions in the riding model approximation (C---H 0.93Å), with their temperature

factors were set to 1.2 times those of the equivalent isotropic temperature factors of

the parent atoms. All other non-H atoms were refined anisotropically. The R factor for

observed data finally converged to R = 0.0742 with wR2 = 0.1990 in the compound.

The maximum and minimum values of residual electron density were 0.874 and -

0.854 eÅ-3. Molecular diagrams were generated using ORTEP [59]. The mean plane



Figure 2.1e shows the chemical diagram of the compound A5. Table 2.1e summarizes



factors for the compound are presented in Table 2.2e anisotropic displacement


119

parameters are given in Table 2.3e. The corresponding bond lengths and angles are

given in Tables 2.4e. The torsion angles for the nonhydrogen atoms are listed in Table

2.5e. Table 2.6e shows the atomic coordinates and isotropic temperature factors for


[61] are tabulated in Table 2.7e. The intra- and intermolecular hydrogen bonds are

listed in Table 2.8e

Fig: 2.2e



The compound crystallizes in monoclinic space group C2/c. The dihedral angle

between fluorobenzyl and imidazothiadaizole is 89.26(5)° which is almost orthogonal.

The nitrophenyl and imidazothiadiazole are planar with only 10.02(7)° between them

and NO2 group is cis to imidazothiadiazole and aryl ring. Specifically, in

nitrobenzene, the nitro group is essentially coplanar with the adjacent aryl ring since

the molecule is highly polar, having significant negative charge on the O atoms, with

minimum energy conformation [80]. The mesomeric interaction between the nitro

group and the aryl ring in nitrobenzene is rather small, so that the C-N bond is to all

intents and purposes a single bond with a correspondingly small barrier to rotation.

Hence, the intermolecular interaction could be quite modest in solid state, if the nitro-

aryl moiety perturbs its planar conformation. The C-N bond distance is 1.461(5) Å in

nitrobenzene. This value is typical of C(aryl) - NO2 distances [81], where the mean

value is 1.468Å. The C-C distances in the nitrated aryl ring are ranging between

1.310(4) Å and 1.374(5) Å. Within the nitrated aryl rings, the C-C-C angle show

significant deviations from 120 . The O-N-O angle is 123.6° which is greater than the


120

ideal trigonal value. This can be attributed to the substantial negative charges on the

paired O atoms in this unit.

The molecular structure is primarily stabilised by weak intramolecular (Fig 2.2e) C7-

H7…N3 hydrogen bond [C7-H7 = 0.930(3)Å, H7…N3 = 2.557(3)Å, C7…N3 =

2.881(4)Å and the angle C7-H7…N3 = 100.87(1)°] leading to the formation of a

pseudo-five-membered hydrogen bonded pattern with Etter’s graph set analysis S(5)

[82], thus locking the molecular conformation and eliminating conformational

flexibility.


The crystal structure is stabilized by intermolecular interactions into three

dimensional framework structure by the combination of C-H…N, C-H…O, C-H…S

and C-H...F. In C-H…N interaction, the molecules are linked by paired C-H…N

hydrogen bonds into centrosymmetric dimers corresponding to Etter’s graph set

notation R22(10) [82], the C-H…S interaction sets a bonded dimers corresponding to

graph set R22(16) which is formed between C21 and S1 of another molecule and C-

H…O interaction generates trifurcated bonds from three donors C1 and C17 of one

molecule and C1 of another molecule to the same acceptor O1 linking the molecule

into zig-zag ribbon structure along ‘b’ axis (Fig 2.3e). The C-H…F interaction

generates bifurcated bonds from two donors, C14 and C16 to the same acceptor, F1

linking the dimers so formed into zig-zag tapes leading to two dimensional network

and also resulting in centrosymmetric dimers corresponding to graph set R22(8) along

‘b’ axis (Fig 2.4e). The molecular packin -

interactions between the nitro benzene and imidazothiadiazole ring systems with C4-

C7 atoms of two molecules being separated by a distance of 3.238(4)Å (Fig 2.5e)

(symmetry code: ½-x, y, -z ).


121

Fig 2.3e

Packing of the molecules in crystal of A5 viewed along ‘b’ axis. Dotted lines

indicates C-H…S (a-a), C-H….N (a1-a1) and C-H…O (a2-a21, a22, a23)

intermolecular interactions.

Fig 2.4e

Packing of the molecules of A5 with dotted lines indicating C-H…F intermolecular interactions generating zig-zag tapes along ‘b’ axis


122

Fig. 2.5e

View of the molecular packing in A5, showing -imidazothiadiazole and nitro benzene rings.


123

Table 2.1eSummary of crystal data, intensity data collection and refinement of A5 compound

Crystal dataC17H11FN4O2SMr = 354.36Monoclinic, C2/ca = 39.941(6)Åb = 5.698(2)Åc = 13.272(5)Å

= 90.880°V = 3020(2) Å3

Z = 8




R[F2 2)]= 0.0742wR(F2) = 0.2283S = 1.1083146 reflections190 parametersH-atom parameters constrained

Dx = 1.559Mgm-3

= 2.04 - 28.58°µ = 0.246mm1

T = 293 (2) K Rectangular, yellow0.4 × 0.35 × 0.3 mm

2733 reflectRint = 0.0847

max = 28.58°h = -52 45k = -l = -

w = 1/[\s^2^(Fo^2^)+(0.1104P)2

+8.5893P]where P = (Fo2 + 2Fc

2)/3

max = 0.001

max = 0.874 e Å–3

min = -0.854 e Å–3



Data deposition



124

Table 2.2eAtomic coordinates (× 104) and equivalent isotropic

displacement parameters (Å2× 103) of A5

________________________________________________________________

Atom x y z U(eq) ________________________________________________________________

C(1) 929(1) 8704(6) 810(2) 25(1) C(2) 1291(1) 7996(6) 887(2) 21(1) C(3) 1818(1) 5890(6) 882(2) 20(1) C(4) 2148(1) 8836(6) 1284(2) 19(1) C(5) 2685(1) 6405(6) 1286(2) 18(1) C(6) 2325(1) 6796(6) 1172(2) 20(1) C(7) 2830(1) 4249(6) 1013(2) 21(1) C(8) 3165(1) 3849(6) 1132(2) 22(1) C(9) 3363(1) 5627(6) 1529(2) 22(1) C(10) 3232(1) 7779(6) 1800(2) 23(1) C(11) 2893(1) 8154(6) 1685(2) 23(1) C(12) 696(1) 6639(6) 885(2) 26(1) C(13) 575(1) 5541(7) 16(3) 29(1) C(14) 369(1) 3612(7) 79(3) 33(1) C(15) 282(1) 2771(7) 1021(3) 31(1) C(16) 399(1) 3791(8) 1894(3) 33(1) C(17) 604(1) 5714(7) 1814(3) 32(1) O(1) 3824(1) 3180(5) 1541(2) 35(1) O(2) 3901(1) 6846(5) 1875(2) 33(1) N(1) 1528(1) 9466(5) 1094(2) 23(1) N(2) 1825(1) 8245(5) 1094(2) 20(1) N(3) 2115(1) 4936(5) 916(2) 19(1) N(4) 3720(1) 5183(5) 1662(2) 24(1) S(1) 1406(1) 5057(2) 691(1) 24(1) F(1) 77(1) 901(5) 1096(2) 43(1) ________________________________________________________________



125

Table 2.3eAnisotropic displacement parameters (Å2×103) of A5

The anisotropic displacement factor exponent takes the form:-2 2[ h2a*2U11+...+2hka*b*U12 ]

_______________________________________________________________________

Atom U11 U22 U33 U23 U13 U12 _______________________________________________________________________

C(1) 28(2) 28(2) 20(2) -2(1) -1(1) 9(1) C(2) 30(2) 22(2) 11(1) 0(1) -1(1) 1(1) C(3) 28(2) 20(2) 13(1) 1(1) 2(1) -1(1) C(4) 28(2) 19(2) 10(1) 0(1) 0(1) -3(1) C(5) 29(2) 21(2) 4(1) 1(1) 0(1) 2(1) C(6) 27(2) 23(2) 9(1) 0(1) -2(1) 1(1) C(7) 27(2) 21(2) 16(1) 0(1) -3(1) -2(1) C(8) 33(2) 22(2) 11(1) 0(1) 1(1) 5(1) C(9) 25(2) 28(2) 14(1) 4(1) 1(1) -1(1) C(10) 31(2) 23(2) 14(1) 2(1) -3(1) -7(1) C(11) 33(2) 20(2) 15(1) -1(1) 0(1) 0(1) C(12) 25(2) 33(2) 18(2) 0(1) 0(1) 7(1) C(13) 30(2) 39(2) 18(2) -3(1) -4(1) 1(2) C(14) 35(2) 38(2) 25(2) -9(2) -8(1) 6(2) C(15) 22(2) 34(2) 36(2) -2(2) -2(1) 3(1) C(16) 31(2) 47(2) 20(2) 4(2) 1(1) -1(2) C(17) 29(2) 46(2) 20(2) -4(2) -5(1) -2(2) O(1) 35(1) 36(2) 33(1) -6(1) -7(1) 10(1) O(2) 28(1) 39(2) 31(1) 1(1) -5(1) -5(1) N(1) 28(1) 26(2) 15(1) 1(1) 2(1) 3(1) N(2) 29(1) 16(1) 14(1) 1(1) 0(1) 4(1) N(3) 24(1) 18(1) 16(1) 1(1) -1(1) -1(1) N(4) 31(1) 30(2) 12(1) 1(1) -2(1) 1(1) S(1) 25(1) 22(1) 25(1) -3(1) -2(1) 1(1) F(1) 41(1) 40(2) 47(1) -3(1) -2(1) -9(1) _______________________________________________________________________

Table 2.4eBond lengths [Å] and angles [°] for non H-atoms of A5

with esds in parenthesis ________________________________________________________________

C(2)-N(1) 1.289(4)C(2)-S(1) 1.755(3)C(3)-N(4) 1.311(4)C(3)-N(2) 1.373(4)C(3)-S(1) 1.720(3)C(4)-N(2) 1.355(4)C(4)-C(6) 1.374(4)C(5)-C(11) 1.392(4)C(5)-C(7) 1.409(4)C(5)-C(6) 1.460(4)C(6)-N(4) 1.388(4)C(7)-C(8) 1.361(4)C(8)-C(9) 1.378(5)

C(9)-C(10) 1.382(5) ________________________________________________________________


126

Table 2.4e. (Contd.)_______________________________________________________

C(9)-N(3) 1.457(4)C(10)-C(11) 1.379(4)C(12)-C(13) 1.387(5)C(12)-C(17) 1.397(5)C(13)-C(14) 1.381(5)C(14)-C(15) 1.384(5)C(15)-F(1) 1.352(4)C(15)-C(16) 1.364(5)C(16)-C(17) 1.379(5)N(1)-N(2) 1.376(4)

N(3)-O(2) 1.220(4)N(3)-O(1) 1.227(4)

C(2)-C(1)-C(12) 112.3(3)N(1)-C(2)-C(1) 122.6(3)N(1)-C(2)-S(1) 117.4(2)C(1)-C(2)-S(1) 120.1(2)N(4)-C(3)-N(2) 112.3(3)N(4)-C(3)-S(1) 139.0(3)N(2)-C(3)-S(1) 108.6(2)C(11)-C(5)-C(7) 118.3(3)C(11)-C(5)-C(6) 120.5(3)C(7)-C(5)-C(6) 121.1(3)C(4)-C(6)-N(4) 111.7)3)C(4)-C(6)-C(5) 128.6(3)N(4)-C(6)-C(5) 119.7(3)C(8)-C(7)-C(5) 121.5(3)C(7)-C(8)-C(9) 118.6(3)C(8)-C(9)-C(10) 122.0(3)C(8)-C(9)-N(3) 118.3(3)C(10)-C(9)-N(3) 119.7(3)C(11)-C(10)-C(9) 119.0(3)C(13)-C(12)-C(17) 118.1(3)C(13)-C(12)-C(1) 120.1(3)C(17)-C(12)-C(1) 121.8(3)C(14)-C(13)-C(12) 120.4(3)C(13)-C(14)-C(15) 119.3(3)F(1)-C(15)-C(16) 117.7(3)F(1)-C(15)-C(14) 120.0(3)C(16)-C(15)-C(14) 122.2(3)C(15)-C(16)-C(17) 117.7(3)C(16)-C(17)-C(12) 122.3(3)C(2)-N(1)-N(2) 107.5(3)C(4)-N(2)-C(3) 107.5(3)C(4)-N(2)-N(1) 133.8(3)C(3)-N(2)-N(1) 118.4(3)O(2)-N(3)-O(1) 123.6(3)O(2)-N(3)-O(9) 117.8(3)O(1)-N(3)-C(9) 118.5(3)C(3)-N(4)-C(6) 103.6(3)C(3)-S(1)-C(2) 88.11(15)

________________________________________________________________


127

Table 2.5eTorsion angles [°] for non H-atoms of A5 with esds in parenthesis

________________________________________________________________

C(12-C(1)-C(2)-N(1) -162.1(3)C(12)-C(1)-C(2)-S(1) 17.9(4)N(2)-C(4)-C(6)-N(3) -0.1(3)N(2)-C(4)-C(6)-C(5) 179.9(3)C(7)-C(8)-C(9)-N(4) 179.5(3)N(4)-C(9)-C(10)-C(11) 178.9(3)C(13)-C(14)-C(15)-F(1) 179.1(3)F(1)-C(15)-C(16)-C(17) -179.1(3)C(1)-C(2)-N(1)-N(2) -179.3(3)S(1)-C(2)-N(1)-N(2) 0.7(3)C(6)-C(4)-N(2)-C(3) 0.3(3)C(6)-C(4)-N(2)-N(1) 179.0(3)N(3)-C(3)-N(2)-C(4) -0.5(3)S(1)-C(3)-N(2)-C(4) 177.43(19)N(3)-C(3)-N(2)-N(1) 179.4(2)S(1)-C(3)-N(2)-C(1) 1.4(3)C(2)-N(1)-N(2)-C(4) 178.0(3)C(2)-N(1)-N(2)-C(3) 0.5(4)N(2)-C(3)-N(3)-C(6) 0.4(3)S(1)-C(3)-N(3)-C(6) -176.6(3)C(4)-C(6)-N(3)-C(3) -0.2(3)C(5)-C(6)-N(3)-C(3) 179.8(3)C(10)-C(9)-N(4)-O(2) -10.4(4)C(8)-C(9)-N(4)-O(2) 169.8(3)C(10)-C(9)-N(4)-O(1) 170.8(3)C(8)-C(9)-N(4)-O(1) -9.1(4)N(3)-C(3)-S(1)-C(2) 178.5(4)N(2)-C(3)-S(1)-C(2) 1.4(2)N(1)-C(2)-S(1)-C(2) -1.2(2)C(1)-C(2)-S(1)-C(3) -178.8(3)

________________________________________________________________

Table 2.6eHydrogen coordinates (× 104) and isotropic


Atom x y z U(eq) ________________________________________________________________

H(1A) 880 9808 1344 30 H(1B) 889 9493 171 30 H(4) 2208(11) 10510(80) 1380(30) 40(12) H(7) 2694 3071 746 25 H(8) 3258 2416 951 26 H(10) 3371 8954 2056 27 H(11) 2801 9586 1874 27 H(13) 634 6115 -613 35 H(14) 288 2881 -502 39 H(16) 341 3199 2520 39 H(17) 684 6426 2401 38 ________________________________________________________________


128

Table 2.7eMean planes through various groups of atoms and deviations (Å) from the plane, in A5.



1 0.799(9) -0.600(2) -0.008(5) -0.061(6)C12* C13* C14*C15*C16*C17*

-0.0029(3)0.0020(4)0.0020(4)

-0.0037(3)0.0028(4)0.0014(4)

2 0.115(5) 0.189(8) -0.975(1) 0.301(4) S1*

C2*C3*C4*C6*

N1*N2*N3*

-0.0029(8)0.0075(3)0.0276(3)-0.0220(3)-0.0167(3)0.0062(2)0.0112(2)0.0177(2)

3 0.165(2) 0.348(1) -0.922(5) 1.473(6) C5* C7*

C8* C9*

C10*C11*

0.0001(3)0.0024(3)-0.0009(3)-0.0031(3)0.0051(3)-0.0038(3)

Dihedral angles formed by LSQ-Planes in A5.

Plane1 Plane2 Angle


Imidazothiadiazole ring Nitrophenyl ring 10.02(7)°


129

Table 2.8eNonbonded interactions and possible hydrogen bonds in A5 (Å, °)


D—H· · ·A D—H H· · ·A D· · ·A D—H· · ·A

C7–H7· · ·N3 0.930(3) 2.557(3) 2.881(4) 100

C7–H7· · ·N3i 0.930(3) 2.904(3) 3.509(4) 123

C8-H8...S1i 0.930(3) 2.936(1) 3.724(3) 143(9)

C1–H1A· · ·O2ii 0.970(3) 2.955(3) 3.651(4) 129(9)

C1–H1B··O2ii 0.970(3) 2.764(3) 3.613(4) 146(2)

C13-H13...O2iii 0.930(4) 2.776(3) 3.614(4) 150

C14-H14...F1iv 0.930(4) 2.713(3) 3.438(5) 140(4)

C16-H16...F1v 0.930(4) 2.822(3) 3.687(5) 155(3)

Symmetry code: (0) x,y,z ( i) -x+1/2,-y+1/2,-z ( ii) -x+1/2,-y+1/2+1,-z (iii) -x+1/2,+y+1/2,-z+1/2 (iv) -x,-y,-z (v) -x,+y,-z+1/2


130

2.7. Crystal and molecular structure of 6-(4-Chlorophenyl)-2-(4-fluorobenzyl)imidazo[2,1-b][1,3,4]thiadiazole (A6)

F

N

S

N

N

Cl

Fig: 2.1f2.7.1. Introduction

The title compound A6 (C17H11ClFN3S), a derivative of Imidazothiadiazole possess

diverse medicinal biological and pharmacological properties due to the presence of

pharmacophoric isothioamide (S–C=N-) unit. The substitution of a hydrogen atom for

a fluorine atom in the tetracyclic ring system of the molecule was found to possess

better antitumour properties. A single crystal x-ray diffraction analysis was carried out

for this compound in order to establish the crystal as well as molecular structure and

to understand the self-aggregation in terms of possible intermolecular interactions.


The title compound was prepared following the procedure given below and as shown in Scheme 2F.

Br

Cl

O

N

S

N

N

F

ClN

S

N

NH2

F

Na2CO3

3

+

21

Dry EtOH, 18hr

A6

Scheme 2F


and p-chloro phenacyl bromide (2) (0.01mol) was refluxed in dry ethanol for 18 hrs.

The excess of solvent was distilled off and the solid hydrobromide salt that separated

was collected by filtration, suspended in water and neutralized by aqueous sodium


recrystallized from ethyl acetate to afford white needles with good yield 70% (3.08g).


131


The X-ray diffraction data for the compound was collected on a Bruker Smart CCD

Area Detector System, using MoK (0.71073Å) radiation for the crystal. Intensity

data were collected up to a maximum of 27.00° in the –

reduced using SAINTPLUS [57]. The structure was solved by direct methods using

SHELXS97 [58] and difference Fourier synthesis using SHELXL97 [58]. The

positions and anisotropic displacement parameters of all non-hydrogen atoms were

included in the full-matrix least-square refinement using SHELXL97 [58] and the

procedure were carried out for a few cycles until convergence was reached. A total of

8553 reflections were collected, resulting in 3238 [R(int) = 0.0549] independent

reflections of which the number of reflections satisfying I I) criteria were 2307.

These were treated as observed. The H atoms were placed at calculated positions in

the riding model approximation (C---H 0.93Å), with their temperature factors were

set to 1.2 times those of the equivalent isotropic temperature factors of the parent

atoms. All other non-H atoms were refined anisotropically. The R factor for observed

data finally converged to R = 0.0540 with wR2 = 0.1394 in the compound. The

maximum and minimum values of residual electron density were 0.484 and -0.419

eÅ-3. Molecular diagrams were generated using ORTEP [59]. The mean plane



Figure 2.1f shows the chemical diagram of the compound A6. Table 2.1f summarizes



factors for the compound are presented in Table 2.2f anisotropic displacement

parameters are given in Table 2.3f. The corresponding bond lengths and angles are

given in Tables 2.4f. The torsion angles for the nonhydrogen atoms are listed in Table

2.5f. Table 2.6f shows the atomic coordinates and isotropic temperature factors for the

hydrogen atoms. The least-squares planes calculated using the programs PARST [61]

are tabulated in Table 2.7f. The intra- and intermolecular hydrogen bonds are listed in

Table 2.8f.


132

The compound A6 has a chloro group substituted at para position of the phenyl ring.

The dihedral angle between fluorobenzyl and imidazo-thiadaizole is 79.54(3)°

indicating that the two are oriented orthogonally. The chlorophenyl and

imidazothiadiazole are coplanar; the dihedral angle is 7.73(4)° between them. The

C3=N3 bond length of 1.330(4)Å confirms it as a double bond. The C2–N1 bond

length of 1.289(4)Å and the N1–N2 bond length of 1.372(3)Å are relatively short,

suggesting some degree of delocalization in the imidazothiadiazole system. The cis

orientation of the fluorobenzyl group and thiadiazole moiety is characterized by the

torsion angle C(12)-C(1)-C(2)-S(1) [-41.5(3)°] in the molecule. The imidazole part of

this imidazothiadiazole system is more resonance stabilized due to the difference in

bond lengths S1-C3 [1.729(3) Å] and S1-C2 [1.750(3) Å]. Additionally, the

imidazothiadiazole entity is as usual planar and rigid. Most of the imidazothiadiazole

derivatives posses near or total planarity locking the molecules conformationally into

pseudo ring moieties, and self-aggregates through weak C-H…N interactions [84-86].

Fig: 2.2f


ellipsoids and the atom-numbering scheme

The molecular structure is primarily stabilised by weak intramolecular C11-H11…N3

hydrogen bond [C11-H11 = 0.930(3)Å, H11…N3 = 2.567(3)Å, C11…N3 =

2.894(4)Å and the angle C11-H11…N3 = 101.13°] leading to the formation of a five-

membered hydrogen bonded pattern with graph set S(5) [82], thus locking the

molecular conformation and eliminating conformational flexibility.


133


Despite the presence of elements like chlorine, sulphur, fluorine etc, there are no

interesting intermolecular interactions in the crystal structure of A6. However, the

molecular packing of this compound is rendered cohesive by molecules linked via two

C-H…N hydrogen bond interactions [85]. The first C-H…N interaction generates

bifurcated bonds from two donors, C1 and C4 to the same acceptor, N3 (Fig 2.3f).

The second C-H…N interaction (Fig 2.4f) forms centrosymmetric head-to-head

dimers corresponding to graph set notation R22(12).

Fig 2.3f: View of the molecular packing in A6, showing bifurcated C-H…N interactions along ‘b’ axis.


134

Fig 2.4f: Packing of the molecules of A6 with dotted lines indicating C-H…N

intermolecular interactions resulting in centrosymmetric dimers along ‘b’ axis.

The - stacking interaction (Fig 2.5f) between the imidazothiadiazole and

benzene rings [86] being separated by a distance of 3.785(2)Å (symmetry code:-½+x,

½+y, ½-z) further strengthens the supramolecular structure. So the supramolecular

aggregation in this structure is limited to the formation of these bifurcation and -

stacking interactions.

Fig. 2.5f: View of the molecular packing in A6, showing -

interactions between imidazothiadiazole and benzene rings.


135

Table 2.1fSummary of crystal data, intensity data collection and refinement of A6

compound

Crystal dataC17 H11ClFN3SMr = 343.80Monoclinic, P21/na = 10.255(4)Åb = 5.618(3) Åc = 26.044(1) Å

= 91.438(8)°V = 1499.9(11) Å3

Z = 4





Dx = 1.566Mgm-3

= 2.15 - 27.26°µ = 2.616 mm1

T = 293 (2) K Rectangular, colourless0.3 × 0.2 × 0.1 mm

2307Rint = 0.0549

max = 27.00°h = -k = -l = -

w = 1/[\s2(Fo2)+(0.0906P)2

+0.0000P] where P=(Fo2+2Fc2)/3'

max = 0.001

max = 0.484 e Å–3

min = -0.419 e Å–3



Data deposition

Crystallographic data for the structure reported here has been deposited with the

Cambridge Data Centre. The deposition number is CCDC 763066.


136

Table 2.2fAtomic coordinates ( × 104) and equivalent isotropic

displacement parameters (Å2× 103) of A6. ________________________________________________________________

Atom x y z U(eq) ________________________________________________________________

C(1) 3046(3) 6269(5) 1296(1) 34(1) C(2) 2047(3) 6861(5) 1685(1) 30(1) C(3) 735(3) 8671(5) 2336(1) 27(1) C(4) -519(3) 5590(5) 2510(1) 30(1) C(5) -1832(3) 7674(5) 3194(1) 28(1) C(6) -829(3) 7527(5) 2806(1) 28(1) C(7) -2727(3) 5824(5) 3266(1) 31(1) C(8) -3680(3) 5964(6) 3628(1) 35(1) C(9) -3751(3) 7989(6) 3930(1) 36(1) C(10) -2888(3) 9841(6) 3873(1) 38(1) C(11) -1924(3) 9681(5) 3506(1) 35(1) C(12) 3274(3) 8174(5) 906(1) 31(1) C(13) 4273(3) 9826(5) 970(1) 36(1) C(14) 4479(3) 11609(6) 616(1) 35(1) C(15) 3666(3) 11708(5) 191(1) 35(1) C(16) 2662(3) 10115(6) 114(1) 37(1) C(17) 2474(3) 8356(6) 471(1) 36(1) N(1) 1211(2) 5319(4) 1840(1) 32(1) N(2) 474(2) 6374(4) 2209(1) 27(1) N(3) -38(2) 9477(4) 2698(1) 29(1) S(1) 1984(1) 9700(1) 1960(1) 34(1) F(1) 3849(2) 13429(3) -164(1) 47(1) Cl(1) -4948(1) 8177(2) 4392(1) 47(1) ________________________________________________________________



137

Table 2.3fAnisotropic displacement parameters (Å2×103) of A6


_______________________________________________________________________

Atom U11 U22 U33 U23 U13 U12 _______________________________________________________________________

C(1) 39(2) 30(2) 32(2) -2(1) -2(1) 8(1) C(2) 34(2) 25(2) 31(2) -1(1) -8(1) 4(1) C(3) 33(2) 18(1) 31(2) -4(1) -9(1) -1(1) C(4) 36(2) 22(2) 31(2) -1(1) -8(1) -1(1) C(5) 29(2) 28(2) 26(2) 1(1) -9(1) 7(1) C(6) 32(2) 24(2) 27(2) -1(1) -11(1) 2(1) C(7) 37(2) 28(2) 28(2) -4(1) -7(1) 2(1) C(8) 31(2) 40(2) 34(2) 5(1) -7(1) 0(1) C(9) 31(2) 41(2) 34(2) 3(1) -7(1) 12(1) C(10) 43(2) 38(2) 32(2) -6(1) -1(1) 13(1) C(11) 36(2) 29(2) 39(2) -6(1) -6(1) 1(1) C(12) 29(2) 32(2) 30(2) -5(1) -1(1) 4(1) C(13) 34(2) 35(2) 37(2) -13(1) -10(1) 4(1) C(14) 30(2) 33(2) 43(2) -11(1) 1(1) -4(1) C(15) 40(2) 31(2) 34(2) -4(1) 8(1) -3(1)

C(16) 39(2) 39(2) 33(2) -1(1) -7(1) -7(1) C(17) 34(2) 38(2) 36(2) 1(1) -2(1) -7(1) N(1) 42(1) 24(1) 31(1) -4(1) -3(1) 7(1) N(2) 34(1) 21(1) 27(1) -2(1) -5(1) 3(1) N(3) 36(1) 22(1) 30(1) -4(1) -2(1) 0(1) S(1) 39(1) 26(1) 39(1) -6(1) 2(1) -1(1) F(1) 57(1) 42(1) 42(1) 4(1) 7(1) -14(1) Cl(1) 41(1) 62(1) 37(1) 5(1) 3(1) 17(1)

_______________________________________________________________________

Table 2.4f

Bond lengths [Å] and angles [°] for non H-atoms of A6with esds in parenthesis.

____________________________________________________________

C(1)-C(2) 1.497(4)C(1)-C(12) 1.498(4)C(2)-N(1) 1.290(4)C(2)-S(1) 1.750(3)C(3)-N(3) 1.327(4)C(3)-N(2) 1.357(4)C(3)-S(1) 1.731(3)C(4)-N(2) 1.372(4)C(4)-C(6) 1.375(4)C(5)-C(11) 1.395(4)C(5)-C(7) 1.402(4)C(5)-C(6) 1.462(4)C(6)-N(3) 1.395(4)

____________________________________________________________


138

Table 2.4f. (Contd.)_______________________________________________________

C(7)-C(8) 1.377(4) C(8)-C(9) 1.386(4)

C(9)-C(10) 1.376(5)C(9)-Cl(1) 1.744(3)C(10)-C(11) 1.395(4)C(12)-C(13) 1.389(4)C(12)-C(17) 1.385(4)C(13)-C(14) 1.382(4)C(14)-C(15) 1.371(4)C(15)-F(1) 1.354(4)C(15)-C(16) 1.375(4)C(16)-C(17) 1.374(4)N(1)-N(2) 1.372(3)

C(2)-C(1)-C(12) 115.0(2)N(1)-C(2)-C(1) 122.3(3)N(1)-C(2)-S(1) 116.9(2)C(1)-C(2)-S(1) 120.8(2)N(3)-C(3)-N(2) 112.4(2)N(3)-C(3)-S(1) 138.7(2)N(2)-C(3)-S(1) 108.9(2)N(2)-C(4)-C(6) 104.6(3)C(11)-C(5)-C(7) 117.8(3)C(11)-C(5)-C(6) 120.5(3)C(7)-C(5)-C(6) 121.6(3)C(4)-C(6)-N(3) 111.4(3)C(4)-C(6)-C(5) 127.5(3)N(3)-C(6)-C(5) 121.1(2)C(8)-C(7)-C(5) 121.8(3)C(7)-C(8)-C(9) 118.9(3)C(10)-C(9)-C(8) 121.1(3)C(10)-C(9)-Cl(1) 119.6(2)C(8)-C(9)-Cl(1) 119.3(2)C(9)-C(10)-C(11) 119.5(3)C(5)-C(11)-C(10) 120.8(3)C(13)-C(12)-C(17) 118.0(3)C(13)-C(12)-C(1) 121.5(3)C(17)-C(12)-C(1) 120.5(3)C(14)-C(13)-C(12) 121.9(3)C(15)-C(14)-C(13) 118.0(3)F(1)-C(15)-C(14) 119.3(3)F(1)-C(15)-C(16) 118.8(3)C(14)-C(15)-C(16) 122.0(3)C(17)-C(16)-C(15) 119.1(3)C(16)-C(17)-C(12) 121.1(3)C(2)-N(1)-N(2) 108.1(2)C(3)-N(2)-C(4) 108.1(2)C(3)-N(2)-N(1) 118.2(2)C(4)-N(2)-N(1) 133.7(2)

C(3)-N(3)-C(6) 103.6(2) C(3)-S(1)-C(2) 87.86(14) _____________________________________________________________


139

Table 2.5f Torsion angles [°] for non H-atoms of A6 with esds in parenthesis

________________________________________________________________

C(12)-C(1)-C(2)-N(1) 139.4(3)C(12)-C(1)-C(2)-S(1) -41.7(3)N(2)-C(4)-C(6)-N(3) -0.7(3)N(2)-C(4)-C(6)-C(5) 179.7(2)C(11)-C(5)-C(6)-C(4) 172.2(3)C(7)-C(5)-C(6)-C(4) -7.8(4)C(11)-C(5)-C(6)-N(3) -7.3(4)C(7)-C(5)-C(6)-N(3) 172.8(2)C(11)-C(5)-C(7)-C(8) 0.5(4)C(6)-C(5)-C(7)-C(8) -179.5(2)C(5)-C(7)-C(8)-C(9) -0.1(4)C(7)-C(8)-C(9)-C(10) -0.2(4)C(7)-C(8)-C(9)-Cl(1) -179.7(2)C(8)-C(9)-C(10)-C(11) 0.0(4)Cl(1)-C(9)-C(10)-C(11) 179.5(2)C(7)-C(5)-C(11)-C(10) -0.7(4)C(6)-C(5)-C(11)-C(10) 179.3(3)C(9)-C(10)-C(11)-C(5) 0.4(4)C(2)-C(1)-C(12)-C(13) 94.8(3)C(2)-C(1)-C(12)-C(17) -84.2(3)C(17)-C(12)-C(13)-C(14) 0.0(4)C(1)-C(12)-C(13)-C(14) -179.0(3)C(12)-C(13)-C(14)-C(15) -0.3(5)C(13)-C(14)-C(15)-F(1) -179.6(3)C(13)-C(14)-C(15)-C(16) 0.6(5)F(1)-C(15)-C(16)-C(17) 179.7(3)C(14)-C(15)-C(16)-C(17) -0.6(5)C(15)-C(16)-C(17)-C(12) 0.2(5)C(13)-C(12)-C(17)-C(16) 0.1(5)C(1)-C(12)-C(17)-C(16) 179.1(3)C(1)-C(2)-N(1)-N(2) 177.5(2)S(1)-C(2)-N(1)-N(2) -1.3(3)N(3)-C(3)-N(2)-C(4) -1.0(3)S(1)-C(3)-N(2)-C(4) -179.92(18)N(3)-C(3)-N(2)-N(1) -179.7(2)S(1)-C(3)-N(2)-N(1) 1.4(3)C(6)-C(4)-N(2)-C(3) 1.0(3)C(6)-C(4)-N(2)-N(1) 179.4(3)C(2)-N(1)-N(2)-C(3) -0.1(3)C(2)-N(1)-N(2)-C(4) -178.3(3)N(2)-C(3)-N(3)-C(6) 0.5(3)S(1)-C(3)-N(3)-C(6) 179.0(3)C(4)-C(6)-N(3)-C(3) 0.1(3)C(5)-C(6)-N(3)-C(3) 179.7(2)N(3)-C(3)-S(1)-C(2) 179.9(3)N(2)-C(3)-S(1)-C(2) -1.7(2)N(1)-C(2)-S(1)-C(3) 1.8(2)C(1)-C(2)-S(1)-C(3) 177.0(2)

_______________________________________________________________


140

Table 2.6fHydrogen coordinates (× 104) and isotropicdisplacement parameters (Å2×103) of A6.

________________________________________________________________

Atom x y z U(eq) ________________________________________________________________

H(1A) 2776 4829 1118 41 H(1B) 3866 5932 1475 41 H(7) -2676 4466 3063 37 H(8) -4266 4719 3669 42 H(10) -2947 11190 4078 45 H(11) -1337 10927 3469 41 H(13) 4818 9729 1260 43 H(14) 5149 12708 665 42 H(16) 2117 10226 -176 45 H(17) 1799 7270 420 43 H(4) -810(30) 3920(60) 2534(11) 40(9) ________________________________________________________________

Table 2.7fMean planes through various groups of atoms and deviations (Å) from the plane, in A6.



1 -0.605(1) 0.420(1) -0.676(9) -2.552(1)C5*C7*C8*C9*C10*C11*

0.003(3)-0.002(3)-0.001(3)0.002(3)0.001(3)-0.003(3)

2 0.628(1) -0.602(1) -0.492(1) -1.856(8) C12* C13*

C14*C15*C16*C17*

0.001(2)-0.001(3)-0.002(3)0.003(3)-0.002(3)-0.001(3)

3 -0.648(4) 0.295(7) -0.701(5) -3.206(5) C2* S1*

C3*N3*C6*C4*N2*N1*

-0.020(3)0.001(1)

-0.009(3)-0.007(2)0.002(2)0.002(3)0.009(2)0.002(2)


141


Plane1 Plane2 Angle


Imidazothiadiazole ring Chlorophenyl ring 7.73(4)°

Table 2.8fNonbonded interactions and possible hydrogen bonds in A6 (Å, °).


D—H· · ·A D—H H· · ·A D· · ·A D—H· · ·A

C11-H11...N3

C1-H1b...N3i

C4-H4...N3ii

0.930(3)

0.970(3)

0.977(3)

2.567(3)

2.571(2)

2.658(4)

2.894(4)

3.431(4)

3.501(4)

101

148

147

Symmetry code: ( 0) x,y,z ( i) -x+1/2,+y-1/2,-z+1/2 (ii) x,+y-1,+z


142

2.8: Crystal and molecular structure of 6-(4-Bromophenyl)-2-(4-fluorobenzyl)imidazo[2,1-b][1,3,4]thiadiazole (A7)

Fig. 2.1g

2.8.1. Introduction

The title compound A7 (C17H11BrFN3S), is an imidazo[2,1-b][1,3,4]thiadiazole

derivative, with significant pharmacological activities and have potential

pharmaceutical prospects. Moreover, presence of fluoro substituent in the molecule

provides enhanced biological activity. These findings prompted us to synthesize the

title compound so that it could be screened for its pharmacological properties and to

carry out its crystal structure elucidation.



2G.

Br

O

+ Br

Dry EtOH, 18hr

Na2CO3

1 2 3

A7

Scheme 2G

A mixture of equimolar quantities of 2-Amino-(4-fluorobenyl)-1,3,4-

thiadiazole 1 (2.69, 0.013mol) and phenacyl bromide 2 (0.01mol) was refluxed in dry

ethanol for 18 hrs. The excess of solvent was distilled off and the solid hydrobromide

salt that separated was collected by filtration, suspended in water and neutralized by

aqueous sodium carbonate solution to get free base 3. It was filtered, washed with

water, dried and recrystallized from ethanol. Good quality single crystals were grown

from a chloroform solution by slow evaporation at room temperature.


143


The X-ray diffraction data for the compound A7 was collected on a Bruker Smart

CCD Area Detector System, using MoK (0.71073Å) radiation for the crystal.

Intensity data were collected up to a maximum of 28.37° in the –

data were reduced using SAINTPLUS [57]. The structure was solved by direct

methods using SHELXS97 [58] and difference Fourier synthesis using SHELXL97

[58]. The positions and anisotropic displacement parameters of all non-hydrogen

atoms were included in the full-matrix least-square refinement using SHELXL97 [58]

and the procedure were carried out for a few cycles until convergence was reached. A

total of 8589 reflections were collected, resulting in 3308 [R(int) = 0.0544]


were 2419. These were treated as observed. The H atoms were placed at calculated

positions in the riding model approximation (C---H 0.93Å), with their temperature

factors were set to 1.2 times those of the equivalent isotropic temperature factors of

the parent atoms. All other non-H atoms were refined anisotropically. The R factor for

observed data finally converged to R = 0.0478 with wR2 = 0.1117 in the compound.

The maximum and minimum values of residual electron density were 0.856 and -

0.731 eÅ-3. Molecular diagrams were generated using ORTEP [59]. The mean plane



Figure 2.1g shows the chemical diagram of the compound A7. Table 2.1g summarizes



factors for the compound are presented in Table 2.2g. Anisotropic displacement

parameters are given in Table 2.3g. The corresponding bond lengths and angles are

given in Tables 2.4g. The torsion angles for the nonhydrogen atoms are listed in Table

2.5g. Table 2.6g shows the atomic coordinates and isotropic temperature factors for


[61] are tabulated in Table 2.7g. The intermolecular hydrogen bonds are listed in

Table 2.8g.


144

Fig 2.2g: ORTEP diagram of compound A7, showing 50% probability

displacement ellipsoids and the atom-numbering scheme. Dotted line indicates

intramolecular C11-H11…N3 interaction

The title compound A7 crystallizes in the monoclinic space group P21/n. In the

molecule, the imidazothiadiazole and bromophenyl rings are individually planar with

maximum deviations of 0.0215(4) and 0.0044(4)Å, for C2 and C9 respectively; the

mean-planes of imidazothiadiazole and bromophenyl makes a dihedral angle of

27.34(3)° with respect to each other. Similar deviations from planarity of

corresponding rings have been reported earlier [87]. The dihedral angle between

fluorobenzyl and imidazothiadiazole is 79.54(3)° which is almost orthogonal. The

average value of the bond distances [1.388(6)Å] and exocyclic bond angles

[120.6(8)°] in the phenyl rings have normal values which agrees quite well with the

values reported in the literature for some analogous structures [61, 62]. The C-N

bond lengths in the imidazole ring are longer than that of a typical C=N bond but

shorter than that of a C-N bond indicating electron delocalisation in the ring. The

thiadiazole moiety displays differences in the bond lengths of the pairs of bonds C1-

N1/C3-N2 and S1-C2/S1-C3 due to the fused imidazole ring as well as the different

groups attached on either sides of the imidazothiadiazole ring system. The difference

in bond lengths S1-C2 [1.758(4)Å] and S1-C3 [1.731(4)Å] indicates that the

resonance effect caused by the imidazole ring is stronger than that caused by the

thiadiazole ring. Additionally, the imidazothiadiazole entity is generally planar and

rigid.


145

In the molecular packing features of the crystal structure, the molecular structure is

primarily stabilized by intramolecular C11-H11…N3 hydrogen bond [C11-H11 =

0.930(4)Å, H11…N3 = 2.590(3)Å, C11…N3 = 2.907(6)Å and the angle C11-

H11…N3 = 100°] leading to the formation of a pseudo-five-membered hydrogen

bonded pattern with graph set S(5), thus locking the molecular conformation and

eliminating conformational flexibility.


The three dimensional framework structure by the combination of C-H…N, C-H…Br

and C-H…F. intermolecular interactions stabilizes the crystal structure. Hydrogen

bonds and - stacking interactions are main non-covalent interactions in structure of

imidazothiadiazole derivative and have great influence effect on the crystal packing.

Amongst various non-covalent interactions that govern molecular arrangement in

crystal structures, those involving halogens have been a matter of debate for many

years [88]. The molecular structure is stabilized by strong C1-H1B…N3 and rather

weak C4-H4…N3 intermolecular interactions resulting in chains of molecules along

the ‘b’ axis [Fig 2.3g].

Fig 2.3g: Packing of the molecules of A7 with dotted lines indicating C-H…N

intermolecular interactions generating chains along ‘a’ axis.


146

The C-H…Br interactions creates self assembly in terms of two dimensional zig-zag

tapes like pattern along crystallographic ‘b’ axis (Fig 2.4g). The pairs of C-H…F.

hydrogen bond interaction links the molecules into centrosymmetric dimers

corresponding to graph set notation R22(8). The presence of the fluoro substituent on

the benzene ring enhances the acidity of the C-H groups. The C-F group does not

favor the formation of F… F contacts as do the C-Cl, C-Br, and C-I groups [76].

Additionally, -

between the fluorobenzyl rings with the shortest centroid–centroid distance 3.645(6)Å

systems (Fig 2.5g) (symmetry code: -2-x, 2-y, 1-z ).

Fig 2.4g: Packing of the molecules A7 with dotted lines indicating C-H…Br

intermolecular interactions generating zig-zag tapes along ‘b’ axis.


147

Fig 2.5g: Packing of the molecules in A7 viewed along ‘b’ axis. Dotted lines

indicates C-H….F intermolecular interactions that result in centrosymmetric

dimmers


148

Table 2.1g

Summary of crystal data, intensity data collection and refinement of A7 compound

Crystal dataC17H11BrFN3SMr = 388.26Monoclinic, P21/na = 10.505(4) Å b = 5.617(2) Åc = 25.877(11) Å

= 91.566(7)°V = 1526.2(11) Å3

Z = 4





Dx = 1.690Mgm-3

on 0.71073 Å= 2.11 - 27.00°

µ = 2.84 mm1

T = 296 (2) K Rectangular, yellow0.18 × 0.16 × 0.16 mm

2419Rint = 0.054

max = 27.00°h = -k = -l = -

2(Fo2) + (0.0630P)2

+0.0000P]where P = (Fo2 + 2Fc

2)/3

max = 0.001

max = 0.86 e Å–3

min = -0.73 e Å–3



Data deposition

Crystallographic data for the structure reported here has been deposited with the Cambridge Data Centre. The reference number is PV2388.


149

Table 2.2gAtomic coordinates ( × 104) and equivalent isotropic

displacement parameters (Å2× 103) of A7. ________________________________________________________________

Atom x y z U(eq) ________________________________________________________________

C(1) -1898(4) 6339(6) 3699(1) 32(1) C(2) -2894(3) 6920(6) 3320(1) 28(1) C(3) -4220(3) 8748(6) 2679(1) 26(1) C(4) -5421(3) 5636(6) 2509(1) 28(1) C(5) -6754(3) 7708(6) 1842(1) 25(1) C(6) -5751(3) 7565(6) 2217(1) 26(1) C(7) -7627(3) 5856(6) 1781(1) 29(1) C(8) -8573(3) 5950(7) 1429(1) 34(1) C(9) -8671(3) 7945(7) 1117(1) 34(1) C(10) -7837(3) 9808(7) 1164(1) 36(1) C(11) -6881(3) 9679(6) 1522(1) 32(1) C(12) -1684(3) 8245(6) 4096(1) 28(1) C(13) -0714(3) 9915(7) 4033(1) 34(1) C(14) -0508(3) 11678(6) 4389(1) 32(1) C(15) -1308(3) 11748(6) 4820(1) 32(1) C(16) -2275(3) 10156(7) 4901(1) 37(1) C(17) -2456(3) 8396(6) 4538(1) 35(1) N(1) -3702(3) 5374(5) 3163(1) 32(1) N(2) -4447(3) 6431(5) 2802(1) 25(1) N(3) -4997(3) 9534(5) 2324(1) 27(1) S(1) -29995(9) 9793(2) 3053(1) 33(1) F(1) -1127(2) 13452(4) 5179(1) 44(1) Br(1) -99661(4) 8078(1) 625(1) 48(1) ________________________________________________________________


Table 2.3gAnisotropic displacement parameters (Å2×103) of A7

The anisotropic displacement factor exponent takes the form:-2 2[ h2a*2U11+...+2hka*b*U12 ]

_______________________________________________________________________

Atom U11 U22 U33 U23 U13 U12 _______________________________________________________________________

C(1) 39(2) 33(2) 24(2) 1(2) 1(2) -10(2) C(2) 36(2) 22(2) 25(2) 4(2) -7(2) -5(2) C(3) 32(2) 19(2) 28(2) 2(1) -8(1) -1(1) C(4) 30(2) 20(2) 33(2) 1(2) -5(1) 2(1) C(5) 25(2) 29(2) 21(2) 0(1) -9(1) -5(1) C(6) 29(2) 20(2) 28(2) -1(1) -10(1) -2(1) C(7) 35(2) 26(2) 26(2) 1(2) -7(2) -2(2) C(8) 31(2) 36(2) 33(2) -3(2) -9(2) 2(2) C(9) 32(2) 43(2) 28(2) -5(2) -7(2) -12(2) C(10) 41(2) 34(2) 32(2) 9(2) -4(2) -14(2)

_______________________________________________________________________


150

Table 2.3g. (Contd.)_______________________________________________________________________

C(11) 34(2) 26(2) 37(2) 6(2) -6(2) -3(2) C(12) 26(2) 28(2) 30(2) 5(2) -1(1) -3(1) C(13) 28(2) 38(2) 34(2) 11(2) -10(2) -2(2) C(14) 29(2) 35(2) 32(2) 11(2) 4(1) 9(2) C(15) 36(2) 33(2) 28(2) 3(2) 8(2) 0(2) C(16) 37(2) 42(2) 30(2) -1(2) -11(2) 9(2)

C(17) 32(2) 37(2) 34(2) 1(2) -5(2) 11(2) N(1) 39(2) 27(2) 29(2) 4(1) -5(1) -5(1) N(2) 32(2) 23(2) 20(1) 4(1) -3(1) -3(1) N(3) 32(2) 23(2) 27(2) 5(1) -4(1) 1(1) S(1) 37(1) 24(1) 37(1) 4(1) 1(1) 2(1) F(1) 54(1) 40(1) 36(1) -6(1) 6(1) 14(1) Br(1) 39(1) 72(1) 32(1) -6(1) 1(1) -21(1)

_______________________________________________________________________

Table 2.4gBond lengths [Å] and angles [°] for non H-atoms of A7

with esds in parenthesis. ________________________________________________________________

C(1)-C(2) 1.490(5) C(1)-C(12) 1.504(5) C(2)-N(1) 1.288(4) C(2)-S(1) 1.761(3) C(3)-N(3) 1.322(4) C(3)-N(2) 1.360(4)

C(3)-S(1) 1.729(4) C(4)-N(2) 1.365(4) C(4)-C(6) 1.371(5) C(5)-C(11) 1.391(5)

C(5)-C(7) 1.399(5) C(5)-C(6) 1.455(5) C(6)-N(3) 1.392(4) C(7)-C(8) 1.368(5) C(8)-C(9) 1.387(5)

C(9)-C(10) 1.373(5) C(9)-Br(1) 1.890(4) C(10)-C(11) 1.386(5) C(12)-C(17) 1.386(5) C(12)-C(13) 1.391(5) C(13)-C(14) 1.374(5)

C(14)-C(15) 1.379(5) C(15)-F(1) 1.351(4) C(15)-C(16) 1.366(5) C(16)-C(17) 1.380(5) N(1)-N(2) 1.369(4)

C(2)-C(1)-C(12) 114.5(3) N(1)-C(2)-C(1) 122.8(3) N(1)-C(2)-S(1) 116.4(3) C(1)-C(2)-S(1) 120.8(3)

N(3)-C(3)-N(2) 112.0(3) N(3)-C(3)-S(1) 139.2(3) N(2)-C(3)-S(1) 108.8(2)

________________________________________________________________


151

Table 2.4g. (Contd.)_______________________________________________________

N(2)-C(4)-C(6) 104.6(3)

C(11)-C(5)-C(7) 116.8(3) C(11)-C(5)-C(6) 121.6(3) C(7)-C(5)-C(6) 121.5(3) C(4)-C(6)-N(3) 111.4(3) C(4)-C(6)-C(5) 127.6(3) N(3)-C(6)-C(5) 121.0(3) C(8)-C(7)-C(5) 122.5(3) C(7)-C(8)-C(9) 119.1(4) C(10)-C(9)-C(8) 120.4(4) C(10)-C(9)-Br(1) 120.2(3) C(8)-C(9)-Br(1) 119.4(3) C(9)-C(10)-C(11) 119.7(3) C(10)-C(11)-C(5) 121.5(3) C(17)-C(12)-C(13) 117.8(3) C(17)-C(12)-C(1) 120.7(3) C(13)-C(12)-C(1) 121.5(3) C(14)-C(13)-C(12) 122.4(3) C(15)-C(14)-C(13) 117.4(3) F(1)-C(15)-C(16) 118.5(3) F(1)-C(15)-C(14) 118.9(3) C(16)-C(15)-C(14) 122.7(3) C(15)-C(16)-C(17) 118.7(3) C(16)-C(17)-C(12) 121.1(3) C(2)-N(1)-N(2) 108.5(3) C(3)-N(2)-C(4) 108.2(3) C(3)-N(2)-N(1) 118.3(3) C(4)-N(2)-N(1) 133.5(3) C(3)-N(3)-C(6) 103.8(3) C(3)-S(1)-C(2) 87.94(17) ________________________________________________________________

Table 2.5gTorsion angles [°] for non H-atoms of A7 with esds in parenthesis

________________________________________________________________C(12)-C(1)-C(2)-N(1) 139.7(3)

C(12)-C(1)-C(2)-S(1) -41.6(4) N(2)-C(4)-C(6)-N(3) -0.1(4) N(2)-C(4)-C(6)-C(5) 179.0(3) C(11)-C(5)-C(6)-C(4) 171.4(3) C(7)-C(5)-C(6)-C(4) -7.8(5) C(11)-C(5)-C(6)-N(3) -9.6(5) C(7)-C(5)-C(6)-N(3) 171.3(3) C(11)-C(5)-C(7)-C(8) 0.5(5) C(6)-C(5)-C(7)-C(8) 179.7(3) C(5)-C(7)-C(8)-C(9) -0.5(5) C(7)-C(8)-C(9)-C(10) 0.6(5) C(7)-C(8)-C(9)-Br(1) -179.4(2) C(8)-C(9)-C(10)-C(11) -0.8(5) Br(1)-C(9)-C(10)-C(11) 179.2(3) C(9)-C(10)-C(11)-C(5) 0.9(5) C(7)-C(5)-C(11)-C(10) -0.7(5) C(6)-C(5)-C(11)-C(10) -179.9(3) C(2)-C(1)-C(12)-C(17) -83.6(4) C(2)-C(1)-C(12)-C(13) 96.2(4) C(17)-C(12)-C(13)-C(14) 0.2(5) C(1)-C(12)-C(13)-C(14) -179.6(3) _______________________________________________________________


152

Table 2.5g. (Contd.)_______________________________________________________

C(12)-C(13)-C(14)-C(15) 0.1(5) C(13)-C(14)-C(15)-F(1) -179.7(3) C(13)-C(14)-C(15)-C(16) 0.1(6) F(1)-C(15)-C(16)-C(17) 179.3(3) C(14)-C(15)-C(16)-C(17) -0.4(6) C(15)-C(16)-C(17)-C(12) 0.7(6) C(13)-C(12)-C(17)-C(16) -0.5(6) C(1)-C(12)-C(17)-C(16) 179.2(3) C(1)-C(2)-N(1)-N(2) 177.4(3) S(1)-C(2)-N(1)-N(2) -1.3(4) N(3)-C(3)-N(2)-C(4) -0.5(4) S(1)-C(3)-N(2)-C(4) -179.3(2) N(3)-C(3)-N(2)-N(1) -179.4(3) S(1)-C(3)-N(2)-N(1) 1.8(3) C(6)-C(4)-N(2)-C(3) 0.3(3) C(6)-C(4)-N(2)-N(1) 179.0(3) C(2)-N(1)-N(2)-C(3) -0.4(4) C(2)-N(1)-N(2)-C(4) -178.9(3) N(2)-C(3)-N(3)-C(6) 0.4(4) S(1)-C(3)-N(3)-C(6) 178.7(3) C(4)-C(6)-N(3)-C(3) -0.2(4) C(5)-C(6)-N(3)-C(3) -179.4(3) N(3)-C(3)-S(1)-C(2) 179.7(4) N(2)-C(3)-S(1)-C(2) -1.9(2) N(1)-C(2)-S(1)-C(3) 2.0(3) C(1)-C(2)-S(1)-C(3) -176.8(3) ________________________________________________________________

Table 2.6gHydrogen coordinates (× 104) and isotropic


Atom x y z U(eq) ________________________________________________________________

H(1A) -7862 4879 3877 38 H(1B) -8898 6044 3512 38 H(4) -4219 4124 2508 33 H(7) -2438 4509 1988 35 H(8) -856 4694 1400 40 H(10) -2088 11151 957 43 H(11) -3688 10939 1549 39 H(13) -9813 9835 3739 40 H(14) -10145 12781 4341 38 H(16) -7197 10256 5194 44 H(17) -6893 7292 4590 42 ________________________________________________________________


153

Table 2.7gMean planes through various groups of atoms and deviations (Å) from the plane, in A7.



1 -0.592(1) -0.424(1) -0.684(1) -2.999(8)C5*C7*C8*C9*

C10*C12*

-0.002(1)-0.001(3)-0.001(3)0.002(2)-0.003(3)-0.003(3)

2 -0.640(4) -0.272(8) -0.717(5) -2.313(6) C2* N1*

N2*C4*C6*N3*C3*S1*

0.024(3)0.002(2)-0.008(2)-0.012(3)-0.001(3)0.012(2)0.012(3)-0.002(1)

30.635(2) 0.602(1) -0.482(3) -8.059(1)

C12*C13*C14*C15*C16*C17*

0.014(3)0.001(3)

-0.001(3)-0.001(3)0.002(3)-0.003(3)

Dihedral angles formed by LSQ-Planes in A7.

Plane1 Plane2 Angle

Imidazothiadiazole ring fluorobenzyl 79.54(3)°

Imidazothiadiazole ring bromophenyl 27.34(3)°


154

Table 2.8gNonbonded interactions and possible hydrogen bonds in A7 (Å, °).


D—H· · ·A D—H H· · ·A D· · ·A D—H· · ·A

C11–H11· · ·N3

C1–H1B· · ·N3i

C4-H4...N3ii

C17–H17· · ·Br1iii

C14–H14··F1iv

0.930(4)

0.97

0.93

0.929(4)

0.929(4)

2.590(3)

2.57

2.74

3.181(2)

2.674(3)

2.907(6)

3.423(5)

3.488(6)

4.067(4)

3.434(5)

100

147

137

159

139

Symmetry code: (0) x,y,z ( i) -x-1/2-1,+y-1/2,-z+1/2 ( ii) x,+y-1,+z (iii) -2-x, 3-y,1-z (iv)-1/2-x, -1/2+y,1/2-z


155

2.6 Summary

The Seven compounds discussed in this chapter, have at their cores, an imidazo[2,

1b][1,3,4]thiadiazole ring system, with an fluorobenzyl group in position 2 (Scheme

2E). The 6-position is occupied by phenyl group in A1. In A2, the morpholinomethyl

group is occupied at position 5 and methoxy phenyl at position 6. The aldehyde group

and phenyl group is attached at position 5 and 6 in A3 respectively. In A4, A5 A6 and

A7 the imidazothiadiazole ring is attached at position 6 to chlorophenyl,

methoxyphenyl, nitrophenyl and bromophenyl moieties respectively.

A1 A2

A3 A4

A5 A6

A7

Scheme 2E

In all the seven

conjugations, owing to their fused nature as well as the groups attached to them. This

is evident from the C-N bond length similarities in imidazole ring (having values

intermediate between those of single and double bonds) as against the C-S bond

length differences in thiadiazole ring. As a result, the imidazole part of this

NN

S N

CH2F N O

OMe

F

S

NN

Cl

N

F

S

NN

OMe

N


156

imidazothiadiazole system is more resonance stabilized. Additionally, the

imidazothiadiazole entity is generally planar and rigid.

The substituted phenyl group in all seven molecules are coplanar with

imidazothiadiazole system. The fluorobenzyl group is non-coplanar due to the

orthogonal orientation with the imidazothiadiazole ring in all seven molecules. The

presence of morpholinomethyl ring decreases the planarity of the molecule. Hence,

the morpholinomethyl ring is almost orthogonal to imidazo-thiadiazole ring in A2.

The coplanarity between imidazothiadiazole and aryl groups seems to depend on the

aryl substituent with nitro group in A6 increasing it whereas the chlorophenyl group

in A4, methoxy group in A5 and bromo group in A7 decreases it. Hence the deviation

from planarity is maximum in A2 due to morpholinomethyl ring.

The morpholinomethyl moiety in A2 adopts a conventional chair

conformation with oxygen and nitrogen atoms deviating from the plane and

occupying apical and base positions respectively. In A1, A2 and A4-A7, there are

intramolecular C-H…N bonds leading to formation of various pseudo membered

rings which lock the molecular conformations. In A3, the molecule is stabilized by

intramolecular C-H…O bonds leading to the formation of a pseudo-seven-membered

hydrogen bonded pattern with graph set S(7), thus locking the molecular

conformation and eliminating conformational flexibility.

The supramolecular aggregation in all the seven crystals is consolidated by

intermolecular C-H…O, C-H…N, C-H…Cl, C-H…Br and C-H…F hydrogen bonded

self–assembly. Additionally, the crystal packing in the molecule A2 highlights a very

interesting molecular packing features on C-H…F interaction where the six molecules

connects themselves into a perfect hexagonal geometry depicting a cyclohexagonal

ring pattern in order to establish the construction of crystalline superstructures. These

interactions link the molecules through dimers and chains producing two dimensional

architectures which are sometimes layered -

interactions, C- -H…S short contacts in the molecules.

In conclusion, all the seven compounds exhibit structural features desirable in

pharmacophores and hence are susceptible to optimum pharmaceutical activity in

biologically conducive environments. The results of their structural studies emphasis

again the facts which cause these heterocyclic systems to be traditional focal points

for the development of good therapeutic agents.


157

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