Andrea
Altieri
a,
Vincent
Aucagne
a,
Romen
Carrillo
a,
Guy J.
Clarkson
b,
Daniel M.
D'Souza
a,
Jennifer A.
Dunnett
b,
David A.
Leigh
*a and
Kathleen M.
Mullen
a
aSchool of Chemistry, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh, EH9 3JJ, United Kingdom. E-mail: David.Leigh@ed.ac.uk; Fax: +44 (0) 131-650-6453; Tel: +44 (0) 131-650-4721
bDepartment of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom
First published on 14th July 2011
We report on the synthesis, structure and properties of [2]rotaxanes prepared by the assembly of benzylic amide macrocycles around a series of amide and sulfide-/sulfoxide-/sulfone-containing threads. The efficacy of rotaxane formation is related to the hydrogen bond accepting properties of the various sulfur-containing functional groups in the thread, with the highest yields (up to 63% with a rigid vinyl spacer in the template site) obtained for sulfoxide rotaxanes. X-Ray crystallography of a sulfoxide rotaxane, 5, shows that the macrocycle adopts a highly symmetrical chair-like conformation in the solid state, with short hydrogen bonds between the macrocycle isophthalamide NH-protons and the amide carbonyl and sulfoxide S–O of the thread. In contrast, in the X-ray crystal structures of the analogous sulfide (4) and sulfone (6) rotaxanes, the macrocycle adopts boat-like conformations with long intercomponent NH⋯OSO and NH⋯S hydrogen bonds (in addition to several intercomponent amide–amide hydrogen bonds). Taking advantage of the different hydrogen bonding modes of the sulfur-based functional groups, a switchable molecular shuttle was prepared in which the oxidation level of sulfur determines the position of the macrocycle on the thread.
An appropriate sulfide thread 3 was synthesised in four steps from commercially available 3-mercapto-propionic acid (see Supporting Information† and Scheme 2). Oxidation of 3 with m-chloroperoxybenzoic acid (MCPBA) could be used to afford either the sulfoxide (4) or sulfone (5) threads in good yields (Scheme 2, step ii). The three threads (3–5) were each subjected to rotaxane-forming conditions5 using equimolar amounts of isophthaloyl dichloride and p-xylylenediamine in CHCl3 in the presence of Et3N, pleasingly yielding the desired [2]rotaxane, 6–8, in each case. The sulfoxide rotaxane 7 was isolated in 43% yield (cf. 62% and 50% for glycylglycine5 and succinamide threads4 using similar rotaxane-forming protocols) whereas the yields of the sulfide 6 (12%) and sulfone 8 (10%) rotaxanes were considerably lower, presumably due to the modest hydrogen bond acceptor ability of those functional groups.
Scheme 2 Synthesis of sulfur-containing hydrogen bonded [2]rotaxanes 6–8. Reagents and conditions: (i) diphenylethanol (1.0 equiv.), bis(chlorodibutyltin)oxide (cat.), toluene, reflux, 8 h, 88% (3); (ii) MCPBA, CHCl3, −20 °C, 90 min, 70% (4, 1.0 equiv. MCPBA), 98% (5, from 4: 1.0 additional equiv. MCPBA); (iii) isophthaloyl dichloride (five-fold excess), p-xylylenediamine (five-fold excess), Et3N (ten-fold excess), CHCl3, RT, 4 h, 12% (6), 43% (7), 10% (8); (iv) MCPBA (1.0 equiv.), CHCl3, −20 °C to RT, 90 min., 95%; (v) MCPBA (1.0 equiv.), CHCl3, −20 °C to RT, 90 min., 97%; (vi) Lawesson's reagent (1.0 equiv.), THF, −20 °C to RT, 1 h, 87%. |
Small crystals of each of the three sulfur-containing rotaxanes 6–8 were obtained by slow diffusion of diethyl ether into saturated solutions of the rotaxanes in methanol (6), dichloromethane (7) or chloroform (8) and their solid state structures determined by X-ray crystallography (Fig. 1–3).17 The crystal structure of the sulfoxide–amide [2]rotaxane 7 (Fig. 1) has features reminiscent of the solid state structures of various bis-amide thread (dipeptide,5fumaramide,4succinamide4) rotaxanes. The benzylic amide macrocycle adopts a low energy chair-like conformation with each isophthalamide group hydrogen bonding to the thread sulfoxide or carbonyl group through four short (2.12–2.56 Å NH⋯O) hydrogen bonds. The isophthalamide–sulfoxide hydrogen binding is sufficiently strong that it overcomes the problem of shape of the sp3-hybridised sulfoxide group, twisting the conformation of the thread in order to ensure the necessary relative positioning of the hydrogen bonding groups.
Fig. 1 X-Ray crystal structure of sulfoxide [2]rotaxane 7. Hydrogen bond lengths (Å): O42–H2N = 2.38; O42–H11N = 2.56; O45–H29N = 2.12; O45–H20N = 2.31. Hydrogen bond angles (°): N2–H2N–O42 = 127.3; N11–H11N–O42 = 142.2; N20–H20N–O45 = 148.7; N29–H29N–O45 = 171.7. |
Fig. 2 X-Ray crystal structure of sulfide [2]rotaxane 6.17Hydrogen bond lengths (Å): S1–H4N = 2.77; O3–H5N = 2.18; O5–H1N = 2.21; O5–H2N = 2.30. Hydrogen bond angles (°): N1–H1N–O5 = 160.6; N2–H2N–O5 = 172.1; N4–H4N–S1 = 151.6; N5–H5N–O3 = 151.3. |
Fig. 3 X-Ray crystal structure of sulfone [2]rotaxane 8.17Hydrogen bond lengths (Å): O38–H2N = 2.15; O10–H42N = 1.97; O41–H20N = 2.07, O41–H29N = 2.22. Hydrogen bond angles (°) N2–H2N–O38 = 143.3; N42–H42N–O10 = 153.5, N20–H20N–O41 = 159.6; N29–H29N–O41 = 175.1. |
In contrast, in the solid state structures of the sulfide–amide (6) and sulfone–amide (8) rotaxanes (Fig. 2 and 3, respectively), the macrocycle adopts relatively high energy conformations that maximise the number of intercomponent amide–amide hydrogen bonds (presumably because amide–sulfide and amide–sulfone hydrogen bonds are intrinsically weak).17 The strength of the amide–amide hydrogen bonding distorts the macrocycle into boat-like conformations with only a single (2.77 Å NH⋯S (6); 2.15 Å NH⋯OS(O) (8)) intercomponent amide–sulfide/sulfone hydrogen bond in each case (together with three intercomponent amide–amide hydrogen bonds).
The difference in hydrogen bonding behavior of these motifs suggested that it might be possible to modulate the strength of the intercomponent binding in such rotaxanes by chemically switching the oxidation level of the sulfur-based functional group. Using MCPBA, the sulfide rotaxane 6 could be oxidised to either the sulfoxide 7 or sulfone 8rotaxanes, depending on the stoichiometry of the peroxy acid used, and the sulfoxide rotaxane 7 similarly converted into sulfone 8 (Scheme 3). However, although sulfoxide 7 could be reduced to sulfide 6 using an excess of Lawesson's reagent ((CH3OC6H4PS2)2),18 chemical reduction of the sulfone rotaxane 8 could not be achieved. The inability to reduce sulfone 8, as well as the modest template ability of the flexible threads, led us to consider the use of a more rigid vinyl sulfoxide-based template. This could allow the substitution of a sulfoxide or sulfone functionality by Michael addition of a nucleophile and subsequent elimination of the sulfoxide/sulfone fragment.19 If the nucleophile used is the thiolate analogue of the rotaxane stopper then this Michael–retro-Michael sequence could be employed to afford the ‘reduced’ sulfide–amide rotaxane (Scheme 3, inset).20
Scheme 3 Synthesis of vinyl sulfur-based hydrogen bonded [2]rotaxanes 9–12. Reagents and conditions: (i) isophthaloyl dichloride (five-fold excess), p-xylylenediamine (five-fold excess), Et3N (ten-fold excess), CHCl3, RT, 3 h, 63% (11); (ii) MCPBA (1.5 equiv.), CH2Cl2, RT, 18 h, 83% (12); (iii) Ph2CHCH2CH2SNa (10 equiv.), DMF, 120 °C, 15 h, 85% (10); (iv) Ph2CHCH2CH2SNa (10 equiv.), DMF, 120 °C, 16 h, 92% (10). Inset: mechanism for the Michael–retro-Michael substitution of the sulfoxide/sulfone stopper group. |
Vinyl sulfoxide–amide thread 9 was prepared in three steps from commercially available building blocks (see the Supporting Information†). The bulky diphenylmethyl group of 9 is positioned further away from the sulfur centre in comparison to threads 3–5 in order to minimise steric interactions between the macrocycle and the stopper. Rotaxane formation using the standard clipping protocol afforded the vinyl sulfoxide rotaxane 11 in 63% yield (Scheme 3), significantly higher than for the flexible sulfoxide thread (4) and similar to that of other well-positioned hydrogen bond acceptors on rigid threads (fumaramide,4bis-nitrone,12azodicarboxamide13).
Oxidation of 11 with MCPBA generated the vinyl sulfone rotaxane 12. Treatment of either 11 or 12 with excess sodium 3,3-diphenylpropan-1-thiolate in hot DMF allowed complete and clean conversion to the vinyl sulfide [2]rotaxane 10. Only a single diastereomer (E) was apparent by 1H and 13C NMR spectroscopy. Presumably Michael addition of the thiolate stopper on the α-β-unsaturated amides of 11 and 12 generates the corresponding amide enolates (Scheme 3, inset), stabilised through hydrogen bonds with the amide macrocycle. Subsequent β-elimination forms the vinyl sulfide rotaxane 10.
The significant difference in binding modes of the amide–sulfur group binding sites led us to incorporate the vinyl sulfur hydrogen bonding motif into a more complex structure in which chemical oxidation/reduction of the sulfur moiety could be used to induced shuttling of the macrocycle between two different sites of the rotaxane thread.21,22 Various external stimuli, including pH,23 metal ions,24 photochemistry,25,26 electrochemistry,27 temperature28 and the reversible formation (and breaking) of C–C bonds,29 have been used to induce shuttling in bistable amide rotaxane switches. However, the use of chemical (rather than electrochemical) oxidation and reduction to induce shuttling in rotaxanes remains rare.13 Here the design of the rotaxane thread consists of both an oxidation-level-tuneable sulfur-based binding site and a flexible succinamide group (Scheme 4). The macrocycle preferentially binds to the sulfoxide moiety over the succinamide station due to the superior hydrogen bonding strength of the S–O bond and the rigidity of the vinyl spacer between the amide and sulfoxide hydrogen bond accepting groups.26 Chemical reduction or oxidation to the corresponding sulfide or sulfone switches off the strong hydrogen bonding to the sulfur functional group and the macrocycle relocates to the succinamide binding site.
Scheme 4 Synthesis and switching of a sulfur–succinamide molecular shuttle. Reagents and conditions: (i) isophthaloyl dichloride (five-fold excess), p-xylylenediamine (five-fold excess), Et3N (ten-fold excess), CHCl3, RT, 23% 14 + 8% 15; (ii) MCPBA (1.0 equiv.), CH2Cl2, −78 °C to RT, 2 h, 90%; (iii) MCPBA (2.0 equiv.), CH2Cl2, −78 °C to RT, 2 h, 92%; (iv) Ph2CHCH2CH2SNa (10 equiv.), DMF, 120 °C, 16 h, 93%; (v) Ph2CHCH2CH2SNa (10 equiv.), DMF, 120 °C, 18 h, 90%; (vi) MCPBA (1.0 equiv.), CH2Cl2, −78 °C to RT, 2 h, 93%; (vii) MCPBA (2.0 equiv.), CH2Cl2, −78 °C to RT, 2 h, 88%. |
The synthesis of a vinyl sulfide–succinamide thread, 13, was achieved in four steps from commercially available starting materials (see the Supporting Information†). Formation of the interlocked architecture using the multi-component clipping reaction furnished a mixture of [2]- and [3]-rotaxanes, 14 and 15, which were separated by flash column chromatography. [2]Rotaxane 14 could be smoothly and selectively oxidised to the corresponding vinyl sulfoxide 16 or vinyl sulfone 17rotaxane, depending upon the stoichiometry of oxidant used. The corresponding sulfoxide and sulfone threads 18 and 19 were prepared by oxidising 13 with MCPBA (Scheme 4).
Comparison of the 1H NMR spectra of the three oxidation states of the vinyl sulfur rotaxanes 14, 16 and 17 in CDCl3 with the corresponding free threads allowed the net position of the macrocycle to be determined in each case. With the vinyl sulfide 14 and vinyl sulfone 17rotaxanes, the chemical shift of the signal corresponding to the ethylene bridge of the succinamide station are significantly shifted upfield (Fig. 4b and 4f, respectively) due to shielding from the xylylene rings of the macrocycle, whereas signals from the vinyl sulfide and sulfone moieties do not undergo large shifts between thread and rotaxane, consistent with the macrocycle being predominantly located over the succinamide binding site. In contrast to rotaxanes 14 and 17, the resonances of sulfoxide rotaxane 16 are broad at room temperature in CDCl3, indicative of slow dynamic processes, presumably a result of stronger intercomponent hydrogen bonding in the sulfoxide shuttle. At 55 °C the resonances are comparable in sharpness to the other rotaxanes at room temperature (Fig. 4d). Modest shielding of the protons of the succinamide station (Δδ 0.2 ppm) occurs in sulfoxide rotaxane 16 (Fig. 4d), accompanied by a much larger shift in the vinyl sulfoxide protons (Δδ 0.7 ppm) indicating that the macrocycle is preferentially located around the vinyl sulfoxide–amide station. Furthermore, the xylylene aromatic protons of the macrocycle (HF) appear as a diastereotopic set in 16 (Fig. 4d) indicating that the macrocycle is held in a well-expressed chiral environment, i.e. in the vicinity of the asymmetric sulfoxide group.
Fig. 4 1H NMR spectra (400 MHz, CDCl3, 25 °C unless otherwise indicated) of (a) sulfide thread 13, (b) sulfide [2]rotaxane 14, (c) sulfoxide thread 18 (55 °C), (d) sulfoxide [2]rotaxane 16 (55 °C), (e) sulfone thread 19, (f) sulfone [2]rotaxane 17. The assignments correspond to the lettering shown in Scheme 4. |
The sulfide-, sulfoxide- and sulfone-containing rotaxanes 14, 16 and 17 could be interconverted by oxidation and Michael–retro-Michael reactions in excellent yields (Scheme 4). Accordingly, the vinyl sulfur–amide system is a chemically-switchable molecular shuttle that could prove useful as a component of more complex molecular machines.
Footnote |
† Electronic supplementary information (ESI) available: Synthesis and characterisation of all compounds. CCDC reference numbers 828037 (6), 829630 (7) and 828038 (8). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c1sc00335f |
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