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Since the majority of tetrafluoro cyclohexane motifs have been found to be crystalline, it was an attractive prospect to study the intermolecular interactions and supramolecular arrangements, which might be dictated by the electrostatic ordering of the cyclohexane rings. X-ray structure analysis should reveal modes of ring stackings. It was also of interest to demonstrate that motif 5.7 is reactive enough to allow its introduction into more complex molecular architectures, and then explore its supramolecular arrangements.

Supramolecular chemistry can be define as ‘’the chemistry of the noncovalent bond’’ where noncovalent interactions account for molecular stability in complexes across nanoscience, including studies in biochemistry and materials.18,19 _{Crystal packing analysis proved to be an}

invaluable tool in the exploration of the forces acting within the solid state of metallic, covalent, ionic, and molecular crystals.20 _{In relation to this research the main interest will}

focus on molecular crystals, where the supramolecular arrangement is dictated by cyclohexane ring stacking. Non-covalent interaction can be classified into two main groups- ‘mostly physical forces’ and ‘mostly chemical forces’.20 _{While physical forces include van der}

Waals non-bonded interaction such as dispersion/ London and repulsive forces, hydrophobic and electrostatic interactions, chemical forces contain hydrogen bonding interactions and charge transfer (CT) interactions, which also include halogen bonding.20

Due to high molecular dipole of the facially polarized tetrafluoro cyclohexane motifs, it is of interest as to whether certain conformations arise due to the specific electrostatic interactions exhibited by these organofluorine motifs and can then dictate the supramolecular arrangement.

For this purpose the generation of bis-systems was envisaged, whereby terephthaloyl bridges would connect two tetrafluoro cyclohexane motifs.

Consequently one objective of this project was to explore the molecular self-assembly of higher order fluorinated bis-amide systems in the solid state, using both tetrafluoro cyclohexane amine derivatives 5.7.a and 5.7.b as the amine components. A comparative ester, rather then an amide was also prepared to compare systems with and without the amide linker, because intermolecular hydrogen bonding between the amides may dominate the packing. The general esterification procedure used to obtain these bis-systems was performed with terephthaloyl chloride in presence of amines 5.7.a, 5.7.b or alcohol 3.9.a (2.1 eq.).

As a result, bis-systems 5.9, 5.10 and the ester 5.11 were obtained in reasonable yields (79%, 48%, and 88%) (Scheme 5.5).21,22 _{A similar reaction was performed with 1,4-phenylene}

diisocyanate in the presence a catalytic amount of triethylamine in toluene and 3.9.a, to furnish 5.12 in 91% yield (Scheme 5.5). 23,24

Cl Cl O O + 5.9 - 5.11 2.1 eq. H N O O N H F F F F F F F F H N O O N H F F F F F F F F 5.9 5.10 O O O O F F F F F F F F F F F F XH 1 eq X O O X F F F F F F F F X= NH/ O y x z 9- 5.11 N N C C 2.1 eq. F F F F HO 1 eq HN C NH C F F F F F F F F O O O O O O i ii 5.12

Scheme 5.5: Synthesis of 5.9-5.11: (i) Terephthaloyl chloride (1 eq.), Et3.N (4 eq.), DMAP (20 mol %), DCM, 18 h, rt, 79% (5.9),

48% (5.10), 88% (5.11) ; Synthesis of 5.12: (ii) Et3N (0.1 eq.), Toluene, 4 h, 60 °C (91 %).

x z y y x z x z y

The bis-compounds 5.9-5.12 were all found to be solids that possessed low solubility in a wide range of solvents and a suitable crystal of each was obtained and subjected to X-ray analysis. The intermolecular packing 5.9, 5.10, 5.11 and 5.12 was analyzed after X-ray crystallography (Scheme 5.4 and Figure 5.5).

Figure 5.5: X-ray structures of compounds 5.9-5.12.

It was immediately clear that the negative fluorous faces and positive protic faces of the tetrafluorocyclohexane rings were orientated relative to each other in all cases (Figure 5.5). The general trend for these compounds is a columnar stacking pattern, where neighboring molecules stuck on top of each other rather.

The less sterically demanding methyl groups relative to the methylene moiety of the cyclohexane moieties all occupy axial positions (Figure 5.6). X-Ray crystallography revealed that for 5.9, 5.11 and 5.12, the methyl is syn to the four fluorine atoms of the ring and is positioned among them occupying an axial orientation. By contrast for compound 5.10, the methyl group is sited on the opposing face to the fluorine atoms in the cyclohexane ring and positions itself between the fluorine faces of two neighboring molecules, without affecting the electrostatic stacking of the facially polarised rings (Figure 5.6).

For compounds 5.9 and 5.10 with carboxamide linker, a significant contribution to the stacking structure appears to come from intermolecular hydrogen bonding between the amide groups, with N-H---O=C distances of 2.04 Å, 2.45 Å (Figure 5.6). Carbamate 5.12,also had a distance between neighboring N-H---O=C of 2.9 Å, indicating a weak hydrogen bonding. y x z 5.9 5.10 5.11 5.12

Even though intermolecular hydrogen bonding between N-H and O=C is observed within those systems and found to bring neighboring molecules together, this is not the defining aspect of the columnar packing pattern. A control comparison was made with ester 5.11 showing that even when there are no hydrogen bonds to link structures, the columnar stacking pattern was still observed. Electrostatic attractions between the cyclohexyl rings appears to be significant. The closest intermolecular distances between fluorine of one cyclohexane ring and the hydrogen atoms on the cyclohexane ring of the nearby molecule were found to be 2.45 Å (5.9), 2.49 Å (5.10), 2.50 Å (5.11), 2.35 Å (5.12) (Figure 5.6). These are too long to indicate F-H hydrogen bonding and suggest that the packing pattern is largely governed by physical electrostatic forces of negative fluorine faces and positive hydrogen faces of neighboring rings.

Figure 5.6: X-ray structures and crystal packing of compounds 5.9, 5.10, 5.11, 5.12.

y x z z x y y x z 5.9 5.10 5.11 5.12 H N O O N H F F F F F F F F H N O O N H F F F F F F F F O O O O F F F F F F F F HN C NH C F F F F F F F F O O O O

5.5. Conclusion.

This study has demonstrated a method for the preparation of a new type of 2,3,5,6- tetrafluorocyclohexane amine motifs. Through a five-step synthesis, where diepoxidation furnished the three diastereoisomers 5.3.a, 5.3.b and 5.3.c, the corresponding diastereoisomers of the fluorinated nitrile derivatives (5.7.a, 5.7.b and 5.7.c) were obtained. Reduction of the 2,3,5,6-tetrafluorocyclohexane nitrile derivatives furnished three tetrafluoro amine isomers, which represent novel building blocks with the potential to be widely used including applications in drug discovery. The reactivity of these building blocks was demonstrated through a set of condensation reactions, whereby amine derivatives 5.7.a, 5.7.b along with the alcohol 3.9.a were used to prepare bis-compounds 5.9-5.12. Each of these bis-compounds was then studied using X-ray crystallography to reveal the architecture of their molecular self-assembly. Firstly the supramolecular arrangement of the

bis-compounds was found to have highly structured columnar stacking pattern rather than an interdigitated assembly, with the fluorinated faces of the cyclohexane moiety containing the protic faces of the adjacent molecules. The supramolecular arrangements of these systems is composed of a range of non-covalent interactions, including hydrogen bonding, repulsive and electrostatic forces. However, in comparison studies of bis-systems with carboximide and carbamate bonds (5.9, 5.10 and 5.12) that participate in hydrogen bonding and ester bis-systems without such interactions (5.11) the columnar stacking pattern is retained, suggesting that the facially polarized fluorinated cyclohexane rings can dictate the supramolecular arrangement.

5.6. References.

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Chapter 6. Conclusion and Future Work.