Record Rate Enhancements for Tetrathiafulvalene Guests in the

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Record Rate Enhancements for Tetrathiafulvalene Guests in the Formation of Bipyridinium- and Diazapyrenium-Based [2]Pseudorotaxanes Michele Bruschini,† Gianfranco Ercolani,‡ Stefano Gallina,† and Paolo Mencarelli*,† †

Dipartimento di Chimica e CNR-IMC, Università di Roma La Sapienza, P. le Aldo Moro, 2, 00185 Roma, Italy Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, Via della Ricerca Scientifica, 00133 Roma, Italy

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S Supporting Information *

ABSTRACT: The catalytic effects of guests 5−7 on the cyclization of 1 and 3 have been measured at 62 °C in MeCN. A record rate acceleration of more than 2000 times has been observed in the cyclization of the tricationic host 3 featuring large diazapyrenium π-surfaces by tetrathiafulvalene guests 6 and 7. The results emphasize the role played by extended π-surfaces in the host and the goodness of a tetrathiafulvalene core in the guest, enhanced by polyethereal side arms.

R

Chart 1

otaxanes are intriguing mechanically interlocked molecules that have played a pivotal role in the advancement of nanoscience and artificial molecular machines research.1,2 Once considered exotic molecules,3 they are now routinely prepared by template-directed syntheses.1,4 In spite of the widespread use of templates in organic synthesis,5 quantitative investigations on the rate enhancements brought about by them are very scanty in the literature. From our previous studies on the template effects of πelectron-rich aromatic molecules in the formation of tetracation hosts,6 we realized that the rate acceleration depends on the strength of the charge-transfer interaction between the π-donor template and the π-acceptor transition state and on the presence of polyoxyethylene side arms on the guest that further strengthen its interaction with the transition state by hydrogen bonding. With the aim at obtaining a strong rate enhancement, we have investigated the template effect of tetrathiafulvalene 5 and tetrathiafulvalene derivatives with one and two tetraoxyethylene side arms, 6 and 7, respectively (Chart 1) in the cyclization reaction of compounds 1 and 3 (Scheme 1). The choice of the guests was suggested by the fact that the tetrathiafulvalene unit shows a strong binding afffinity toward the tetracationic cyclophane 2 even in the absence of polyethereal side arms.7,8 Substrate 3 was chosen for the large π-surface of its diazapyrenium units promising a strong π−π © XXXX American Chemical Society

interaction with the guests to be compared with substrate 1 whose smaller bipyridinum units serve as reference. We have previously evaluated the template effect of guest 5 on the cyclization reaction of compound 1,6g and now we have extended our study by taking into consideration the effects of guests 6 and 7 on the cyclization reaction of precursor 1 and of guests 5−7 on the cyclization reaction of precursor 3. The cyclization reactions give [2]pseudorotaxanes 8−13 as products (Chart 2). We report the results of this investigation here. The first-order rate constants (k0) for the cyclization reaction of precursors 1 (k0 = 8.3 × 10−7 s−1) and 3 (k0 = Received: July 13, 2018

A

DOI: 10.1021/acs.joc.8b01786 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 1

Figure 1. Catalytic effects of the templates 5−7 on the cyclization reaction of the precursors 1 and 3. The curves are calculated by fitting the experimental points to eq 1.

Chart 2

conditions of substrate saturation, even higher rate accelerations could be obtained. The kinetic plots in Figure 1 show the results of fitting the experimental points to eq 1. The equation was obtained by considering the guest binding of the substrate (Ksub) and of the cyclic transition state (KT#).6a 1 + KT #[guest] kobs = k0 1 + K sub[guest]

(1)

Equation 1 indicates that a rate increase will be observed if KT# > Ksub.10,11 The binding constants Ksub and KT#, obtained by the fitting procedure, are reported in Table 1. The plots in Figure 1 tend to reach a plateau, as predicted by eq 1.12 The plateau value, corresponding to the ratio KT#/Ksub (Table 1), would be achieved when the acyclic precursor is completely saturated by the guest. These values indicate that the guest-saturated precursors 1 and 3 react faster than the free ones. The increase of rates can be ascribed to the larger binding affinity of the cyclic transition states than the acyclic precursors for the guests 5−7. This effect is a consequence of the preorganization of the ring-shaped transition state and of a developing positive charge on the nucleophilic nitrogen. Before deepening the discussion on the values reported in Table 1, it is useful to recall that two structural characteristics of the guest are especially important for the high stability of the complexes, i.e., an aromatic core, capable of interacting by π−π stacking interactions with the host cavity,6e and two polyethereal side arms interacting by [C−H···O] hydrogen bonding with the α-hydrogens of the pyridinium rings.13a Solid-state studies indicate that also the hydrogens of the methylene groups of the p-phenylene spacers of the host are acidic enough to interact, by [C−H···O] hydrogen bonding, with the oxygens of the polyethereal chain.13b We may observe that, for a given precursor, the KT# value increases on going from guest 5 to 7. This behavior is clearly due to the increasing number of side chains, none in 5, one in 6, two in 7. From the data in Table 1, it also appears that, in going from 1 to 3, all of the values of the binding constants

2.1 × 10−6 s−1), obtained at 62 °C in deuterated MeCN without any guest molecule, are from literature.6a,h The first-order kinetics in the presence of variable excess amounts of the guests 5−7 were performed at 62 °C in MeCN by UV−vis spectroscopy, following the charge-transfer band of the [2]pseudorotaxane relative to precursor 1 at λ 830, and that relative to precursor 3 at λ 820 nm. The rate constants kobs were obtained by nonlinear least-squares fits to a first-order rate equation of the kinetic data (absorbance vs time), reported in the Supporting Information. The kobs/k0 ratios, reported in Figure 1 for precursor 1 and 3, as a function of the concentration of 5−7, are a measure of the rate increases caused by the guests. A record rate enhancement of 2300 and 2500 times at a template concentration still far from saturation has been measured in the cyclization of 3 by the guests 6 and 7, respectively. To date, these are the largest reported template effects. Previously reported largest rate enhancements regard the cyclization reaction of 1 templated by 1,5-dinaphtho[38]crown-10 to yield the corresponding catenane, accelerated by about 1900 times,6c and the formation of benzo-18-crown-6 in methanol at 25 °C, accelerated by strontium ion by about 1200 times.9 Calculated kinetic profiles suggest that under B

DOI: 10.1021/acs.joc.8b01786 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

Table 1. Binding Constants for Templates 5−7 in the Cyclization Reaction of the Substrates 1 and 3 in MeCN at 62 °C reactant 1

3

guest 5 6 7 5 6 7

a

Ksub (M−1) 5.0 1.1 3.9 1.6 3.6 4.6

× × × × × ×

102 103 103 103 103 103

a

Reference 6g. isolated as a yellow-brown oil: 1H NMR (300 MHz, CD3CN) δ 2.78 (t, J = 5.7, 1H), 3.48−3.62 (m, 16H,), 4.29 (d, J = 1.1 Hz, 2H), 6.42 (t, J = 1.1 Hz, 1H), 6.47 (s, 2H); ES-MS m/z = 410 [M]+; m/z = 411 [M+1]+ + [M + H]+. Anal. Calcd for C15H22O5S4: C, 43.88; H, 5.40; S, 31.23%. Found: C, 44.05; H, 5.42; S, 31.12. Kinetic Measurements. Kinetics were carried out spectrophotometrically at 62 °C by following the increase of the charge-transfer band at λ 830 for precursor 1 and at λ 820 nm for precursor 3. In a typical run, 100 μL of a 0.010 L−1 mol MeCN solution of 13+·3PF6 or 33+·3PF6 was added to a cell containing a 2.5 mL MeCN solution of known concentration of the template 5, 6, or 7. All of the kinetics showed first-order behavior. Catalytic effects as measured by kobs/k0 ratios, where k0 = 8.3 × 10−7 s−1 for precursor 1 and 2.1 × 10−6 s−1 for precursor 3, at the various guest concentrations given in parentheses in L−1 mol, were as follows (note that concentrations were corrected for the volume increase at 62 °C): Precursor 1 and Guest 6: 1 (0), 55.6 (2.52 × 10−2), 101.8 (5.03 × 10−2), 144.8 (7.48 × 10−2), 184.0 (1.00 × 10−1). Data reported in Figure 1. Precursor 1 and Guest 7: 1 (0), 83.0 (1.00 × 10−2), 271.1 (3.95 × 10−2), 393.6 (5.75 × 10−2). Data reported in Figure 1. Precursor 3 and Guest 5: 1 (0), 246.7 (1.00 × 10−2), 437.1 (2.00 × 10−2), 676.2 (4.02 × 10−2), 847.6 (6.08 × 10−2). Data reported in Figure 1. Precursor 3 and Guest 6: 1 (0), 961.9 (5.21 × 10−3), 1414.3 (1.02 × 10−2), 1947.6 (1.85 × 10−2), 2281.0 (2.54 × 10−2). Data reported in Figure 1. Precursor 3 and Template 7: 1 (0), 1733.3 (1.97 × 10−3), 1838.1 (2.28 × 10−3), 2523.8 (3.88 × 10−3), 2490.4 (4.10 × 10−3). Data reported in Figure 1.

increase probably because of the larger π-surface of the diazapyrenium unit. The effect is more significant for the ringshaped transition states (KT#) than for the acyclic precursors (Ksub). However, the increase of the KT# value, in going from precursor 1 to precursor 3, is not the same for the three guests. The increase is 58 times for guest 5, 106 times for guest 6, and 186 times for guest 7. Such increases correspond (at 62 °C) to ΔΔG values of −2.7, −3.1, and −3.5 kcal/mol, respectively. For a given guest, on going from precursor 1 to precursor 3, the more extended π surfaces of the diazapyrenium units should increase the π−π stacking interactions, whereas the [C−H···O] hydrogen-bonding interactions should remain the same. Since the aromatic core of the guests is the same tetrathiafulavelene unit, all guests should benefit of about the same increase in the energy interaction on going from precursor 1 to 3. However, as noted above, the ΔΔG values are different and appear to be related to the number of the polyethereal chains. In particular, the ΔΔG value seems to increase by about 0.4 kcal/mol for each chain added. As we pointed out in a previous paper,6i a possible explanation for this unexpected behavior can be found by considering that in the 2,7-diazapyrenium unit the hydrogen atoms in the 4,5,9,10 positions (H4) are in a more exposed position than the hydrogen atoms in the β position of the bipyridinium unit. Moreover, whereas the C−Hα and C−Hβ bonds of the bipyridinium unit point in different directions, the C−H3 and C−H4 bonds of the 2,7-diazapyrenium unit are parallel; therefore, the H4 hydrogen atoms, in the 2,7-diazapyrenium unit, may also contribute to the hydrogen-bond interactions. In conclusion, a spectacular rate enhancement of 3 orders of magnitude has been observed in the templated cyclization of the tetracationic host 3 featuring large diazapyrenium πsurfaces by tetrathiafulvalene guests 6 and 7 provided with one and two tetraoxyethylene side arms, respectively. Substitution of bipyridinium with diazapyrenium subunits in the substrates leads to significant rate enhancements evidencing that the larger π-surface of the host implies stronger π−π interactions with the guest in the ring-shaped transition state. Furthermore, it appears that the hydrogen atoms of the type H4 of the 2,7diazapyrene unit may play a role in the hydrogen bonding interactions with the oxygens of the polyethereal chains.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01786. 1

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H NMR spectrum of compound 6 (300 MHz, CD3CN) and the experimental kinetic data for the reactions of precursor 1 in the presence of templates 6, and 7 and of precursor 3 in the presence of templates 5−7 (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

EXPERIMENTAL SECTION

ORCID

Materials and Methods. Substrates 13+·3PF6 and 33+·3PF6 were from our previous work.6a,h 4,4′(5′)-Bis[2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxymethylene]tetrathiafulvalene 7 was prepared as described in the literature.14 Tetrathiafulvalene, 5, and acetonitrile (HPLC grade) were commercial samples used as received. 4-[2-(2-(2(2-Hydroxyethoxy)ethoxy)ethoxy)ethoxymethylene]tetrathiafulvalene, 6, was prepared starting from 4-(hydroxymethyl)tetrathiafulvalene15 by following the same procedure described in the literature for compound 7.14 Starting from 0.500 g (2.13 mmol) of 4-(hydroxymethyl)tetrathiafulvalene, 0.409 g (yield 46.8%) of 6 was

Gianfranco Ercolani: 0000-0003-2437-3429 Paolo Mencarelli: 0000-0002-3172-8294 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS P.M. thanks the Università di Roma “La Sapienza” for financial support (Progetti di Ateneo Federato 2008 and 2009). C

DOI: 10.1021/acs.joc.8b01786 J. Org. Chem. XXXX, XXX, XXX−XXX

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F.; Venturi, M.; Williams, D. J. A Three-Pole Supramolecular Switch. J. Am. Chem. Soc. 1999, 121, 3951−3957. (8) (a) Asakawa, M.; Ashton, P. R.; Balzani, V.; Credi, A.; Hamers, C.; Mattersteig, G.; Montalti, M.; Shipway, A. N.; Spencer, N.; Stoddart, J. F.; Tolley, M. S.; Venturi, M.; White, A. J. P.; Williams, D. J. A Chemically and Electrochemically Switchable [2]Catenane Incorporating a Tetrathiafulvalene Unit. Angew. Chem., Int. Ed. 1998, 37, 333−337. (b) Collier, C. P.; Mattersteig, G.; Wong, E. W.; Luo, Y.; Beverly, K.; Sampaio, J.; Raymo, F. M.; Stoddart, J. F.; Heath, J. R. A [2]Catenane-Based Solid State Electronically Reconfigurable Switch. Science 2000, 289, 1172−1175. (9) Ercolani, G.; Mandolini, L.; Masci, B. Model System for the Template Effect of Alkali and Alkaline-Earth Metal Ions on the Formation of Benzo-18-crown-6 in MeOH Solution. J. Am. Chem. Soc. 1983, 105, 6146−6149. (10) Cacciapaglia, R.; Mandolins, L. Catalysis by Metal Ions in Reactions of Crown Ether Substrates. Chem. Soc. Rev. 1993, 22, 221− 231. (11) Kraut, J. How Do Enzymes Work? Science 1988, 242, 533−540. (12) Only the curve relative to guest 5 with precursor 1 does not show any appreciable tendency to saturation. For a discussion, see ref 6g. (13) (a) Asakawa, M.; Brown, C. L.; Menzer, S.; Raymo, F. M.; Stoddart, J. F.; Williams, D. J. Structure-Reativity Relationship in Interlocked Molecular Compounds and in Their Supramolecular Model Complexes. J. Am. Chem. Soc. 1997, 119, 2614−2627. (b) Houk, K. N.; Menzer, S.; Newton, S. P.; Raymo, F. M.; Stoddart, J. F.; Williams, D. J. [C-H···O] Interactions as a Control Element in Supramolecular Complexes: Experimental and Theoretical Evaluation of Receptor Affinities for the Binding of BipyridiniumBased Guests by Catenated Hosts. J. Am. Chem. Soc. 1999, 121, 1479−1487. (14) Asakawa, M.; Ashton, P. R.; Balzani, V.; Credi, A.; Mattersteig, G.; Matthews, O. A.; Montalti, M.; Spencer, N.; Stoddart, J. F.; Venturi, M. Electrochemically Induced Molecular Motions in Pseudorotaxanes: A Case of Dual-Mode (Oxidative and Reductive) Dethreading. Chem. - Eur. J. 1997, 3, 1992−1996. (15) Garin, J.; Orduna, J.; Uriel, S.; Moore, A. J.; Bryce, M. R.; Wegener, S.; Yufit, D. S.; Howard, J. A. K. Improved Syntheses of Carboxytetrathiafulvalene, Formyltetrathiafulvalene and (Hydroxymethyl)tetrathiafulvalene: Versatile Building Blocks for New Functionalised Tetrathiafulvalene Derivatives. Synthesis 1994, 1994, 489−493.

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DOI: 10.1021/acs.joc.8b01786 J. Org. Chem. XXXX, XXX, XXX−XXX