Tetrameric Cyclic Double Helicates as a Scaffold for a Molecular Solomon Link

A Solomon link, colloquially termed a “Solomon knot” (a link in Alexander–Briggs notation[1]), is a topology of two interwoven rings that cross each other four times in the simplest representation (Figure 1).[2] Such doubly-entwined [2]catenanes are still rare,[3–5] with only two small-molecule examples with wholly organic backbones reported[4,5] to date. The Solomon link is the most complex topology to have been produced[4] using Sauvage’s pioneering route[6] of generating higher order interlocked structures through the connection of the termini of linear double-stranded metal helicates. In principle,[2b,d] cyclic double helicates[7] can provide the crossings required for a range of topologies, while simultaneously positioning connecting sites in close proximity to aid the macrocyclization reactions that can be problematic when employing long linear helicates[8] (Figure 1). A small-molecule pentafoil knot (five crossings) was recently prepared using a pentameric circular helicate scaffold.[9] Here we report on the use of a tetrameric circular helicate as the basis for a Solomon link, illustrating the general utility of this approach for the assembly of complex molecular topologies. 
 
 
 
Figure 1 
 
Ring-closing cyclic metal double helicates for the formation of topologically complex molecules. A pentameric circular double helicate is the scaffold (five crossings) required for a pentafoil knot,[9] and a tetrameric circular double helicate (four crossings) ... 
 
 
 
The ligand used in our earlier synthesis of a pentafoil knot[9] was based on a tris(bipyridine) motif employed[7a,b,d] by Lehn to assemble penta- and hexameric cyclic helicates, but with both outer bipyridine units replaced by 2-formylpyridine groups that could condense with amines to form imines and generate tris(bidentate) ligand strands. As well as providing a convenient way of connecting metal binding components, imine bond formation is reversible, imparting an ‘error checking’ mechanism during the assembly process.[10] Incorporating an additional oxygen atom in the ethylene spacer between each bipyridine group of Lehn’s tris(bipyridine) ligand led to cyclic tetrameric helicates.[7b] Accordingly, in an attempt to generate the four crossings required for a Solomon link, we introduced a similar structural change to the ligand used in the pentafoil knot synthesis in the form of 1 (for the synthesis of 1 see the Supporting Information) and investigated its coordination chemistry with primary amines and FeII salts (Scheme 1). 
 
 
 
Scheme 1 
 
Synthesis of cyclic and linear iron(II) helicates. Reaction conditions: a) FeX2, RCH2NH2, DMSO, 60 °C, 24 h; b) excess KPF6 (aq). DMSO=dimethyl sulfoxide. 
 
 
 
The reaction of 1 with n-hexylamine and FeCl2 (DMSO, 60 °C, 24 h, Scheme 1)[8] produced an intensely colored purple solution typical of low-spin iron(II) tris(diimine) complexes. After 24 hours, the product was isolated in 47 % yield as the hexafluorophosphate salt 2 by precipitation with aqueous KPF6. Electrospray ionization mass spectrometry (ESI-MS; see the Supporting Information, Figure S1) revealed that 2 was a metal–ligand tetramer with the formula [Fe4L4](PF6)8][11] (L=bis(imine) ligand resulting from the condensation of 1 with two molecules of n-hexylamine). 1H NMR spectroscopy (Figure 2 a) indicated that 2 was highly symmetrical, with the splitting of the diastereotopic CH2-O-CH2 protons consistent with the chiral (racemic) helicate topology shown in Scheme 1. The yield of 2 was increased to 71 % (yield of isolated product) when employing 4.4 equivalents of the iron(II) salt (see the Supporting Information, Figure S9). 
 
 
 
Figure 2 
 
1H NMR spectra (CD3CN, 500 MHz) for a) cyclic tetramer 2, b) linear triple helicate 3 (green, signals marked * correspond to trace amounts of 2), c) a 1:1 mixture of cyclic tetramer 4 (black) and linear triple helicate ... 
 
 
 
The formation of the tetrameric cyclic helicate was not limited to the use of FeCl2 as the iron(II) salt (Scheme 1), both Fe(BF4)2 and Fe(ClO4)2 also produced 2, although in significantly lower yields (see the Supporting Information, Figure S13) and contaminated with other polymeric and oligomeric by-products. When FeBr2 was employed as the iron source, a different main product was obtained (Scheme 1), which was identified as the linear trinuclear triple helicate ([Fe3L3]6+) 3 by 1H NMR spectroscopy (Figure 2 b) and ESI-MS (see the Supporting Information, Figure S14). A linear triple helicate with a lifetime of a few minutes was previously observed as an intermediate during the formation of pentameric cyclic helicates using Lehn’s tris(bipyridine) ligand.[7d] While 3 is a much longer-lived species, it is not clear whether this is because the linear triple helicate is particularly stable as the bromide salt, or whether the assembly/disassembly/rearrangement of the various linear and circular helicates and oligomers is markedly slower using FeBr2, perhaps as a result of their limited solubility. 
 
Substituting n-hexylamine for 4-methylbenzylamine in the reaction of 1 with FeCl2 gave a mixture of two species (Figure 2 c), identified by ESI-MS (Supporting Information, Figures S3 and S5) as the cyclic tetramer 4 and the linear triple helicate ([Fe3L3]6+) 5 (Scheme 1). Using our standard reaction protocol with an initial concentration of 1 of 2.2 mm, the ratio of 4/5 was approximately 1:1, however the distribution of cyclic-double-helicate/linear-triple-helicate was significantly altered by small variations in concentration: using an initial concentration of 8.8 mm of 1, more than 95 % of the reaction product was the higher order (four ligands, four metal ions) circular helicate 4 after 24 hours, whereas starting with a concentration of 0.55 mm of 1, the reaction produced more than 85 % of the lower nuclearity (three ligands, three metal ions) linear helicate 5 over the same time period (Supporting Information, Figure S15).[12] In contrast, the yield of the analogous n-hexylamine-derived cyclic tetramer 2 was essentially invariant over this concentration range and no linear triple helicate was observed, illustrating the influence that subtle changes in the ligands can have over the outcomes of the self-assembly reactions. 
 
In order to link the end groups of the open cyclic helicate to generate a Solomon link, we employed 2,2′-(ethylenedioxy)bis(ethylamine), a diamine that is stereoelectronically predisposed to adopt low-energy turns.[9] The reaction of 1 with the diamine and FeCl2 in DMSO for 24 hours, with subsequent anion exchange with aqueous KPF6, generated the Solomon link 6 in 75 % yield of isolated product (Scheme 2).[13] 
 
 
 
Scheme 2 
 
Synthesis of molecular Solomon link 6. Reaction conditions: a) FeCl2, 2,2′-(ethylenedioxy)bis(ethylamine), DMSO, 60 °C, 24 h; b) excess KPF6 (aq), 75 % (over two steps). 
 
 
 
The 1H NMR spectrum (CD3CN, 500 MHz, Figure 2 d) of 6 is very similar to that of the tetrameric cyclic helicate 2 derived from n-hexylamine (Figure 2 a), including the splitting pattern for the diastereotopic CH2-O-CH2 protons. ESI-MS (Supporting Information, Figure S7) confirmed that 6 had a structural formula consistent with a Solomon link. Single crystals of 6 suitable for X-ray crystallography were grown by slow diffusion of diethyl ether into a nitromethane solution of 6, and the structure was confirmed by X-ray crystallography (Figure 3). The solid-state structure shows the two organic macrocycles interlocked by the four crossings that define the topology of a Solomon link. The iron atoms are close-to-coplanar and lie on the vertices of a square with Fe–Fe distances of just over 1 nm. Despite the high yield, as for the related pentafoil knot,[9] the octahedral coordination geometry of the iron(II) centers is amongst the most distorted [Fe(N-ligand)6] structures in the Cambridge Structural Database[14] (see the Supporting Information for details). The -OCH2CH2O- units in the linking group adopt close-to-gauche conformations (59–73°). Two PF6− counter ions are positioned directly above and below the center of the helicate (Figure 3 a) and form bifurcated CH⋅⋅⋅F interactions with the eight Ha protons, which are particularly electron-poor because of the ligand coordination to the iron(II) dications (Supporting Information, Figures S16 and S17). 
 
 
 
Figure 3 
 
X-Ray crystal structure of Solomon link 6. a) Viewed in the plane of FeII ions (all but two PF6− anions omitted); b) viewed from above the center of the macrocycle cavities (all PF6− anions omitted). The C atoms of one ... 
 
 
 
The one-pot synthesis of molecular Solomon link 6 assembles four iron(II) cations, four bis(aldehyde) and four bis(amine) building blocks to generate two interwoven 68-membered-ring macrocycles with four crossings in 75 % isolated yield. The assembly process for the tetrameric cyclic double helicate forms the basis for the Solomon link synthesis and is sensitive to structural changes in the amine, the concentration and the anion used (even though the reaction product is not the result of an anion-template mechanism). The synthesis of Solomon link 6 and the earlier pentafoil knot[9] show that cyclic helicates of different sizes can act as highly efficient and effective scaffolds for intricate molecular topologies.


S2
Compound S2 was prepared according to a modified literature procedure. S2 S1 (1.0 g, 5.4 mmol) and TBDMS-Cl (850 mg, 5.6 mmol) were suspended in DMF (4 mL) and Et 3 N (1.1 mL, 8.0 mmol) was added. The reaction mixture was stirred for 30 min at RT before being quenched by addition of water (50 mL) and Et 2 O (20 mL).
The organic layer was washed with water (3 × 20 mL), then brine (20 mL), dried (MgSO 4 ), filtered under gravity and the solvent was removed in vacuo to give a yellow oil (1.6 g, quant.). Spectroscopic data match those reported in the literature S2  quality to be used in the next step without further purification.

S3
S3 was prepared using a different synthetic route to that reported previously. S3

S2
(1.0 g, 3.3 mmol) was dissolved in Et 2 O (30 mL) and cooled to -78 ºC. n-Butyl lithium (1.5 mL, 2.5 M in hexanes, 3.7 mmol) was slowly added to the reaction. The resulting mixture was stirred for 1 h at -78 ºC before DMF (0.8 mL) was added and the reaction was left to stir for a further 1 h at -78 ºC. Once warmed to r.t. the mixture was quenched with water (20 mL). The organic layer was washed with water (3 × 30 mL), then brine (30 mL), dried (MgSO 4 ), filtered under gravity and the solvent was removed in vacuo. The crude mixture was dissolved in MeOH (20 mL) and cooled to 0 ºC. NaBH 4 (0.11 g, 3.0 mmol) was slowly added. The solution was stirred for 15 min at r.t. before being quenched by addition of water (20 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (3 × 30 mL), then brine (30 mL), dried (MgSO 4 ), filtered under gravity and the solvent was removed in vacuo The product was purified by flash chromatography (SiO 2 , 4:1, DCM: EtOAc) to give S3 as yellow crystals (710 mg, 85 %, over two steps). Spectroscopic data matched those reported in the literature S3

S6
S5 (160 mg, 3.0 mmol) was dissolved in THF (5 mL) and TBAF (1.85 mL, 1 M solution in THF, 1.85 mmol) was slowly added. The resulting solution was stirred for 2 h at r.t. before being quenched by addition of sodium citrate (10 mL, sat. aq. solution) and EtOAc (10 mL) was added. The organic layer was washed subsequently with sodium citrate (10 mL, sat. aq. solution) and water (3 × 10 mL). After drying and removal of the volatile compounds the crude product was recovered as a yellow oil.

1
To a solution of oxalyl chloride (65 mg, 0.51 mmol) in DCM (1 mL) at -78 ºC was slowly added DMSO (88 mg, 1.12 mmol) in DCM (1 mL). The mixture was stirred for 15 min at -78 ºC before a solution of S6 (110 mg, 0.23 mmol) in DCM (2 mL) was slowly added and the reaction was stirred for 1 h at -78 ºC. After addition of Et 3 N (230 mg, 2.3 mmol) the mixture was stirred for a further 30 min at -78 ºC before being allowed to warm to 0 ºC and quenched with water (5 mL). The organic layer was washed with water (3 × 5 mL), then brine (5 mL

SI-Section 4: Effect of FeCl 2 stoichiometry on the formation of circular helicate 2
A solution of dialdehyde 1 (5 mg, 11 μmol, 5 eq.) in DMSO-d 6 (2.5 mL) was The resulting dark purple reactions were thoroughly mixed and heated at 60 °C for one day. After cooling to room temperature, the following work up was performed on each sample separately: excess saturated aqueous KPF 6 was added (5 mL). A fine suspension of a purple material formed which was collected on Celite, thoroughly washed with water, a little ethanol (soluble), and diethylether. The purple solids were dissolved in acetonitrile and concentrated under reduced pressure to give 2 as a purple powder. Each sample was dissolved in CD 3 CN (0.5 mL) and relative yields analyzed by 1 H NMR ( Figure S9). A preparatory synthesis was carried out following the above procedure using 10 mg of 1 (22 μmol), and 4.0 eq of FeCl 2 , gave 15 mg of 2 (71 %).

SI-Section 5: Effect of AgPF 6 addition to remove residual chloride
A small contamination of chloride anions still present after anion exchange causes the signal of H a to become very broad. Addition of small amounts of AgPF 6 caused a dramatic sharpening of the peak as seen in Figures S10-S12. All other signals were unaffected by the addition. A small quantity of AgPF 6 (~0.1 eq) was added in CD 3 CN solution to samples of 2, 4/5 and 6. 1 HNMR spectra were recorded before and after addition.   μmol, 2.2 eq.) was added to each separate sample. All samples were heated at 60 ºC overnight. After cooling to room temperature, the following work up was performed on each sample separately: excess saturated aqueous KPF 6 was added (5 mL). A fine suspension of a purple material formed which was collected on Celite, thoroughly washed with water, ethanol, and diethylether. The purple solid was dissolved in acetonitrile and concentrated under reduced pressure. Each sample was analyzed by 1 H NMR see Figure S13.

Figure S14
: LRESI-MS analysis of 3. A small amount of circular helicate 2 was evident (see Figure S1). To a solution of dialdehyde 1 (5 mg, 11.0 μmol, 5 eq.) in DMSO-d 6 (1.25 mL) was added a solution of anhydrous FeCl 2 (125 μL of 97 mM, 12.1 μmol, 5.5 eq. solution of 4-methylbenzylamine (25 μL of a 190 mM, 4.8 μmol, 2.2 eq.). The resulting dark purple solutions were thoroughly mixed and heated at 60 °C for one day. After cooling to room temperature, the following work up was performed on each sample separately: excess saturated aqueous KPF 6 was added (5 mL). A fine suspension of a purple material formed which was collected on Celite, thoroughly washed with water, ethanol, and diethylether. The purple solid was dissolved in acetonitrile and concentrated under reduced pressure. The products were analyzed by reported above. When the reaction was carried out at concentrations outside the range reported above addition polymeric and oligomeric material was found to contaminate the recovered products.

SI-Section 8: X-Ray Crystallography
Crystal data for Solomon link 6    Figure S17. Side view of 6 with PF 6 (shown in space-filling model) counter ions, above and below the plane of the four iron(II) ions.