Switching of recognition first and reaction first mechanisms in

Subscriber access provided by Nottingham Trent University

Article

Switching of recognition first and reaction first mechanisms in host–guest binding associated with chemical reactions Yoko Sakata, Munehiro Tamiya, Masahiro Okada, and Shigehisa Akine J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06926 • Publication Date (Web): 02 Sep 2019 Downloaded from pubs.acs.org on September 2, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Switching of recognition first and reaction first mechanisms in host–guest binding associated with chemical reactions Yoko Sakata,†‡ Munehiro Tamiya,† Masahiro Okada,† and Shigehisa Akine*†‡

†Graduate

School of Natural Science and Technology, Kanazawa University, Kakuma-machi,

Kanazawa 920-1192, Japan ‡WPI

Nano Life Science Institute (WPI-NanoLSI), Kanazawa University Kakuma-machi,

Kanazawa 920-1192, Japan

ACS Paragon Plus Environment

1

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 33

ABSTRACT: Host–guest binding sometimes triggers the subsequent chemical reactions of the host framework as well as the changes in the physical properties. Since the host–guest binding generally occurs very quickly, it is sometimes difficult to differentiate the mechanism from the alternative one in which the guest binding occurs after the reaction. However, it should be important to differentiate the two mechanisms when we develop new molecules based on timedependent functions. Thus, we propose two distinct mechanisms, recognition first and reaction first, in a slowly reacting host system. We designed and synthesized a new cobalt(III) metallohost, [LCo2(pip)4](OTf)2 (pip = piperidine), which can take up a guest cation in its 18-crown-6-like cavity causing concomitant exchange of the axial piperidine ligands under solvolytic conditions. We investigated the mechanism to elucidate whether the guest recognition or ligand exchange occurs first. When Na+ (5–10 equiv) was present, the guest recognition occurred by the recognition first mechanism, i.e., Na+ was initially taken up into the cavity, then the axial piperidine ligands were replaced with methoxo ligands. On the other hand, when 1 equiv of M+ (= K+, Rb+) was present, the guest recognition occurred by the reaction first mechanism, i.e., M+ was taken up after one of the piperidine ligands was replaced with a methoxo ligand. Therefore, the recognition pathway can be switched by changing the guest cations.


2

Page 3 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


INTRODUCTION Host–guest binding is recognized as an important first step that causes responsive functions of various kinds of functional molecules. If the host molecule carries a chromophore, a fluorophore, or a redox active site, the guest binding would change its color, fluorescence, or redox potentials.1 Host–guest binding could also have a significant influence on the reactivities of the host and guest molecules, not only in stoichiometric/catalytic formation/cleavage of covalent bonds2,3 but also in the formation/disruption of noncovalent interactions.4 Allosteric host molecules are the typical examples because the first guest binding causes a structural change that enhances the binding with the second guest.5 In some cases, the first guest binding and the subsequent reaction appear to occur in a very short period of time. In particular, guest uptake/release processes are generally very fast.6,7 This makes it difficult to differentiate the mechanism from the alternative one in which the guest binding occurs after the reaction. For example, “induced-fit binding” in enzymes8 and artificial hosts9 is known as the guest/substrate binding phenomenon that causes the conformational change for the subsequent functions. In enzyme/substrate systems, however, there is an alternative pathway, “conformational selection”, in which the substrate binding occurs after adopting a conformation suitable for the substrate binding.10 In practical, the conformational interconversion and the guest binding in enzymes and artificial host molecules are so fast that it does not seem to be necessary to differentiate whether the conformational change and guest binding occurs first.11 Nevertheless, increasing attention has been recently focused on the differentiation between the two processes, the induced-fit and conformational selection, depending on whether the guest binding or reaction (conformational change) takes place first.12,13 Analogous two alternative mechanisms are found in


3


Page 4 of 33

redox-active host–guest systems, as to whether the guest binding or electrochemical reaction occurs first.14 This problem can be generalized as a question whether the reaction or recognition occurs first upon the guest binding of a “reactive host” molecule. While the differentiation of the two mechanisms does not seem to be important when both the reaction and recognition processes are quickly completed, the differentiation should be important when we develop new molecules based on time-dependent functions. Thus, we now propose two distinct mechanisms, recognition first and reaction first (Figure 1a) in a slowly reacting host system. We used a new cobalt(III)containing metallohost [LCo2X4]2+ (X = axial ligands) as a model case, in which the guest binding is associated with the ligand exchange reaction15 on the cobalt(III) centers. The ligand exchange reaction occurs in the timescale of minutes to hours, which is easily observable using usual spectroscopic methods and would be useful as the platform of time-dependent functional molecules. Here we report an interesting switching of the two mechanisms, recognition first and reaction first, by changing the guests and their amounts.

Figure 1. (a) Schematic illustration of two distinct mechanisms, recognition first and reaction first, in host–guest binding. (b) Design of macrocyclic host [LCo2(pip)4]2+ with reactive sites.


4

Page 5 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


RESULT AND DISCUSSION Design and synthesis of the metallohost In this study, we used the cobalt(III) metallohost [LCo2X4]2+ (X = axial ligand),16 which has an 18-crown-6-like cavity for cation binding as well as two [Co(saloph)X2] moieties (H2saloph = N,N'-disalicylidene-o-phenylenediamine) for the ligand exchange reactions. This complex is wellsuited for studying the problems whether the recognition or reaction occurs first. The reasons are: (1) Chemical reaction of the host molecule can occur simultaneously with the guest recognition. In the present system, [LCo2X4]2+ can recognize a cationic guest in the crown-ether-like cavity and would undergo ligand exchange reactions on the cobalt(III) centers, and (2) The reaction processes are slow enough to be monitored by spectroscopic methods. Since the low-spin d6 cobalt(III) is generally inert, the exchange of the axial ligand X in [LCo2X4]2+ is sufficiently slow. As the axial ligand, we used piperidine (abbreviated hereafter as pip in the formula), which can be easily replaced by another ligand. In the present case, the piperidine ligands in [LCo2(pip)4]2+ can be slowly replaced by methoxo ligands in methanol under solvolytic conditions (Figure 1b and Figure S1). The metallohost [LCo2(pip)4](OTf)2 was synthesized by the complexation of the bis(saloph) macrocyclic host H4L17 with cobalt(III) acetate under aerobic conditions in the presence of piperidine. The complex was characterized by spectroscopic techniques (Figure S2a). A crystallographic analysis revealed that four piperidine ligands coordinate to the low-spin diamagnetic octahedral cobalt(III) centers in the saloph coordination sites, while the 18-crown-6like cavity remains vacant (Figure 2a and Table S1). In the 1H NMR spectrum in CD3CN, the imine protons were observed as a singlet at 8.58 ppm and the aromatic protons were observed as


5


Page 6 of 33

five signals, which is consistent with the structure in the crystalline state with two [Co(saloph)X2] moieties in the equivalent environment.

Figure 2. Crystal structures of (a) [LCo2(pip)4](OTf)2 with thermal ellipsoids plotted at the 50% probability level, (b) [LCo2(pip)2(OMe)2•Na(MeOH)2](OTf) with thermal ellipsoids plotted at the 30% probability level, and (c) [LCo2(pip)2(OMe)2•K(MeOH)2](OTf) with thermal ellipsoids


6

Page 7 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


plotted at the 30% probability level. Hydrogen atoms, solvent molecules, and triflate anions are omitted for clarity.

Cation Recognition Behavior While

the

metallohost

[LCo2(pip)4](OTf)2

differs

from

the

previously

reported

[LCo2(MeNH2)4](OTf)216 only in the axially coordinating amine ligands, it showed a completely different complexation behavior in the 18-crown-6-like cavity. We observed almost no spectral change immediately after the addition of 1.0 equiv of NaOTf in CD3OD, but after 3 h, we observed a new set of signals in the 1H NMR spectra, indicating the formation of a new species (Figure 3a). It was rather unexpected that this new set of signals was not ascribed to the simple host–guest complex [LCo2(pip)4•Na]3+ but to the [LCo2(pip)2(OMe)2•Na]+ with two methoxo ligands, which was clearly evidenced by the ESI-TOF mass spectra (m/z = 1029.2) (Figure S3). This is in striking contrast to the methylamine-based [LCo2(MeNH2)4](OTf)2, which can recognize guest ions without ligand exchange. Obviously, Na+ was entrapped in the cavity with the concomitant ligand exchange of piperidine with the methoxo ligands. Indeed, the X-ray crystallographic analysis clearly showed the structure of [LCo2(pip)2(OMe)2•Na]+, in which a Na+ ion was located in the central O6 cavity and two methoxo ligands coordinated to the cobalt(III) centers (Figure 2b and Table S1). In this complex, the two methoxo ligands are introduced at the diagonal position and are hydrogen bonded to two methanol molecules coordinating to the Na+ in the central cavity. From the time-course analysis of the 1H NMR spectra, we identified a mono-substituted intermediate, which has three piperidine ligands and one methoxo ligand (Figure 3a). We assigned this species as a Na+ complex [LCo2(pip)3(OMe)•Na]2+ rather than its guest-free form [LCo2(pip)3(OMe)]+, because the 1H NMR chemical shifts were significantly different from those


7


Page 8 of 33

of the corresponding mono-substituted intermediate observed in the absence of Na+ (see below; Figure S4). Consequently, the first ligand exchange is associated with the guest binding, and the second ligand exchange occurs by keeping the guest Na+ in the cavity (Figure 3b). On the other hand, the starting complex [LCo2(pip)4]2+ showed no chemical shift changes in the presence of NaOTf before the ligand exchange occurred. This indicated that the starting complex [LCo2(pip)4]2+ exists almost exclusively as its guest-free form rather than as the Na+ complex. There should be an intermediate species [LCo2(pip)4•Na]3+ or [LCo2(pip)3(OMe)]+ before the formation of [LCo2(pip)3(OMe)•Na]2+, but we observed neither of them in the time-course changes of the 1H NMR spectra. Therefore, we could not directly determine the mechanism of the guest binding as whether recognition first or reaction first from the intermediate analysis. However, even if the intermediate is unobservable, the kinetic study of the ligand exchange of the cobalt(III) metallohost in the absence/presence of a guest cation would provide an insight into the mechanisms as shown in the enzyme–substrate binding systems.12


8

Page 9 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. (a) 1H NMR spectral change of [LCo2(pip)4](OTf)2 in CD3OD after the addition of 1 equiv of NaOTf. See Figure 1b for signal assignments. (b) The scheme of axial ligand exchange of [LCo2(pip)4]2+ in methanol in the presence of NaOTf. There are two possible pathways during the formation of [LCo2(pip)3(OMe)•Na]2+ depending on whether Na+ recognition or ligand exchange occurs first.

Kinetic Study of Ligand Exchange


9


Page 10 of 33

Since the guest was taken up simultaneously with the first step ligand exchange, we investigated the kinetics of the solvolytic ligand exchange of [LCo2(pip)4]2+ in order to determine whether this step occurred by the recognition first or reaction first mechanism (Figure 3b). Actually, [LCo2(pip)4]2+ underwent a slow solvolytic ligand exchange even in the absence of the guest Na+ (Figure 4a). Upon dissolution of [LCo2(pip)4](OTf)2 in CD3OD, two new sets of signals appeared in the 1H NMR spectra. These two sets can be ascribed to the methoxo-substituted derivatives, [LCo2(pip)3(OMe)]+ and [LCo2(pip)2(OMe)2]. The ESI-TOF mass spectra recorded 12 h after dissolution in methanol no longer showed a peak at m/z = 1263.4 for [LCo2(pip)4 + OTf]+, but peaks at m/z = 1007.2 for [LCo2(pip)2(OMe)2 + H]+ and 1029.2 for [LCo2(pip)2(OMe)2 + Na]+ (Figure S2b). It is noteworthy that the diagonal isomer of [LCo2(pip)2(OMe)2] was selectively formed among the three possible isomers of the disubstituted species. The ligand exchange reaction yielding the disubstituted complex [LCo2(pip)2(OMe)2] can be described as a two-step reaction in which the intermediate is the mono-substituted complex [LCo2(pip)3(OMe)]+ (Figure 4b). Since the concentration of methanol is almost constant during the solvolysis, each step can be treated as a pseudo first-order reaction. From the non-linear curve fitting analysis of the mole fractions versus time after dissolution, the rate constants were determined to be k1obs = 2.1 × 10–4 s–1 and k2obs = 1.6 × 10–4 s–1, where k1obs and k2obs are defined as k1[MeOH] and k2[MeOH], respectively (Figure 4c and Figure S5). Since the ligand exchange occurred even in the absence of a guest cation, we cannot exclude the reaction first mechanism in Figure 3b.


10

Page 11 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. Time-course analysis of ligand exchange of piperidine with methoxo ligands in [LCo2(pip)4]2+ in the absence/presence of NaOTf. (a) Reaction scheme of the axial ligand exchange in [LCo2(pip)4]2+ in methanol in the absence of NaOTf. (b) 1H NMR spectral changes (imine proton)

in

the

absence

of

NaOTf

(blue

diamonds,

[LCo2(pip)4]2+;

red

squares,

[LCo2(pip)3(OMe)]+; green triangles, [LCo2(pip)2(OMe)2]). (c) Plots of mole fractions of the three components versus time after dissolution in CD3OD in the absence of NaOTf. (d) Reaction scheme of the axial ligand exchange of [LCo2(pip)4]2+ in methanol in the presence of NaOTf. (e) 1H NMR spectral changes (imine proton) in the presence of 10 equiv of NaOTf (blue diamonds, [LCo2(pip)4]2+; red squares, [LCo2(pip)3(OMe)•Na]2+; green triangles, [LCo2(pip)2(OMe)2•Na]+). (f) Plots of mole fractions of the three components versus time after dissolution in CD3OD in the presence of NaOTf.

We then investigated whether the guest recognition or the ligand exchange occurs first when the guest Na+ is present (Figure 4d). We expected that the detailed analysis of the kinetic data and the Na+-concentration dependence would clarify the mechanism because this system satisfies the rapid equilibrium approximation, i.e., the guest-binding step is fast and reversible on the time scale of


11


Page 12 of 33

the ligand exchange processes. In fact, one can easily distinguish the induced-fit and conformational selection mechanisms in protein–ligand binding systems by the analysis of the ligand concentration dependence of the kinetics of the structural changes. Acceleration is observed with the increase of the ligand concentration in the induced-fit binding, whereas no acceleration is observed in the conformational selection mechanism.12a,b We determined the pseudo-first-order rate constants for each step of the ligand exchange (k1obs and k2obs) in the presence of Na+ (5.0, 7.5, 10 equiv) by non-linear curve fitting (Figures 4e, 5a and Figure S6-8). When 10 equiv of Na+ was present, the first-step exchange was accelerated by 60 times (k1obs = 1.3 × 10–2 s–1). The plots of k1obs versus Na+ concentration clearly showed that the first-step exchange was accelerated in proportion to the Na+ concentration (Figure 5a). Thus, we can conclude that the first-step ligand exchange and guest recognition by [LCo2(pip)4]2+ occurred by the recognition first mechanism. Interestingly, the rates of the first- and the second-step exchange showed a different dependence on the Na+ concentration. The presence of 5 equiv of Na+ significantly accelerated the second-step exchange (k2obs: 13 times), but any further increase in the Na+ concentration did not significantly affect the rates (Figure 5b). This suggests that 5 equiv of Na+ was sufficient to completely convert the mono-methoxo derivative [LCo2(pip)3(OMe)]+ into the Na+ complex [LCo2(pip)3(OMe)•Na]2+, which does not interact with extra Na+ during the second-step ligand exchange. This can explain the fact that k2obs was almost constant when the Na+ concentration was increased from 5 to 10 equiv. The acceleration effect of the Na+ binding on the ligand exchange can be explained by the solvent coordination to the guest Na+ cation. When a cationic guest is trapped in the binding site, solvent molecules can coordinate to the cation and are more likely to approach the [Co(saloph)(pip)2]+


12

Page 13 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


moieties. This may accelerate the ligand exchange reaction on the cobalt(III) centers in the metallohost.

Figure 5. Na+ concentration dependence of the kinetic parameters of the Na+ recognition process by [LCo2(pip)4]2+. (a) Plots of k1obs versus the equivalent of Na+. (b) Plots of k2obs versus the equivalent of Na+.

Switching between Recognition First and Reaction First Mechanisms by Guest Ions As already discussed, the presence of the guest Na+ had a significant acceleration effect on the ligand exchange kinetics in [LCo2(pip)4]2+. This clearly indicated that the ligand exchange proceeded by the recognition first mechanism, although the intermediate [LCo2(pip)4•Na]3+ was not observable in the NMR spectra. However, we expected that we can switch the binding mechanism from the recognition first to the reaction first by reducing the amount of Na+ because the formation of the host–guest complex becomes less favorable. We have already described that the presence of 5 equiv of Na+ caused a significant acceleration of k1obs. When the amount of Na+ was reduced to 1 equiv, the ligand exchange became slower but the acceleration was still observed. Under these conditions, we used the initial rates kini instead of k1obs for comparison, because the


13


Page 14 of 33

pseudo first-order approximation is no longer applicable. The kini in the presence of 1 equiv of Na+ was still more than twice as high as that in the absence of Na+ (Table 1 and Figure S11). In contrast, the presence of 1 equiv of K+ or Rb+ had no acceleration effect on the kini (Table 1 and Figure S12-13), although a similar two-step ligand exchange took place to give [LCo2(pip)3(OMe)•M]2+ then [LCo2(pip)2(OMe)2•M]+ (M = K or Rb) (Figure S9-10). The structure of the final product [LCo2(pip)2(OMe)2•K]+ was confirmed by X-ray crystallography (Figure 2c and Table S2). These facts mean that the first ligand exchange in the presence of K+ and Rb+ mostly occurred in the guest-free form. Nevertheless, the product of the first step should be the guest-bound forms [LCo2(pip)3(OMe)•M]2+ (M = K, Rb), because these were observed at different chemical shifts from those of the guest-free analogue [LCo2(pip)3(OMe)]+ in the 1H NMR spectra. Therefore, this reaction mainly occurred by the reaction first mechanism, i.e., the ligand exchange took place before the uptake of the guest K+ or Rb+ (Figure 3b). This is further confirmed by the fact that the ligand exchange was accelerated when K+ and Rb+ was increased to 10 equiv (Figure S14-15). Obviously, this acceleration is due to the substantial contribution of the recognition first mechanism. This also indicates that there is only a small contribution of the recognition first mechanism in the presence of 1 equiv of K+ and Rb+. Thus, the mechanism was switched by changing the guest cations and their amount (Figure 6). When 1 equiv of weaker guest M+ (= K+, Rb+) is used, the formation of the transient [LCo2(pip)4•M]3+ should become less favorable and the ligand exchange would occur more predominantly without forming the host–guest complex, which can be interpreted as the reaction first mechanism. In fact, the corresponding inert analogue [LCo2(MeNH2)4](OTf)2 [ref 16], which does not undergo ligand exchange, showed a weaker binding with K+ and Rb+ than with Na+.


14

Page 15 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Such a metal-ion-dependent switching of the binding mechanism is known in biomolecular systems. For example, folding of a riboswitch coupled with ligand binding occurs by an inducedfit mechanism in the absence of Mg2+, while the addition of Mg2+ generally shifts the folding mechanism towards conformational selection.12f The mechanistic study of this system would provide an unprecedented insight into the intricate synergy between the ligand- and Mg2+-mediated RNA folding. The present system using [LCo2(pip)4]2+ is the first artificial system in which we can switch the guest binding mechanisms, recognition first and reaction first, depending on the guest cations. Such a dissection would give us a further and general insight into the kinetics of structure conversions triggered by host–guest complexation, which are widely used in artificial responsive functional molecules.

Table 1. Initial rate kini of ligand exchange in [LCo2(pip)4](OTf)2 in the presence/absence of 1 equiv of alkali metal ions. guest cation

Na+

K+

Rb+

none

Initial rate kini (s–1)

4.29(9) × 10–4

1.7(2) × 10–4

1.7(1) × 10–4

1.9(4) × 10–4


15


Page 16 of 33

Figure 6. Switching of the mechanisms, recognition first versus reaction first, depending on the guest cations and their amount.

CONCLUSION We have proposed two new distinct mechanisms, recognition first and reaction first, in host– guest binding associated with chemical reactions. We studied the ligand exchange reaction of a cobalt(III) metallohost, [LCo2(pip)4](OTf)2, which can take up a guest cation in its 18-crown-6like cavity and can undergo exchange of the axial piperidine ligands under solvolytic conditions. The recognition first mechanism was suggested when Na+ was present, while the reaction first mechanism was suggested in the presence of 1 equiv of K+ and Rb+. Therefore, the recognition pathway can be switched by changing the guest cations and their amount. There could be an analogous question in artificial allosteric host systems as to whether the guestbinding occurs in the induced-fit or the conformational selection mechanism as discussed in the well-established theory of protein–ligand binding systems. However, since both of the conformational change and guest recognition processes are completed within a very short period


16

Page 17 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of time, it has been no need to differentiate which process occurs first, and therefore the guest binding associated with a conformational change has been almost solely interpreted as induced-fit mechanism without considering the alternative mechanism, conformational selection. In the present [LCo2(pip)4]2+ system, the reactions associated with the guest binding are relatively slow and easily observable, and thus this enables the detailed kinetic analysis to clarify whether the guest binding or the reaction occurs first and to demonstrate the switching between the recognition first and reaction first mechanisms. We believe that the results reported in this paper will provide a new insight into the kinetics of various kinds of structure conversions that are triggered by host–guest complexation. While the chemistry of responsive functional molecules triggered by host–guest complexation is attracting increasing interest, there has been almost no study on the precise control of their time-course changes. Nevertheless, the synergy of the guest-binding and chemical reactions would be important in designing functional molecules that can release/capture bioactive species, such as toxic metal ions and molecules, upon chemical stimulation, and we are convinced that the understanding of the mechanism would help in developing new time-programmable guest uptake/release systems such as drug delivery systems.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website. Experimental details and additional data, including Tables S1 and S2 and Figures S1–S15 (PDF)


17


Page 18 of 33

X-ray crystallographic data for [LCo2(pip)4](OTf)2, [LCo2(pip)2(OMe)2•Na(MeOH)2](OTf)•2MeOH, and [LCo2(pip)2(OMe)2•K(MeOH)2](OTf)•2.5MeOH•Et2O (CIF).

AUTHOR INFORMATION Corresponding Author *[email protected] Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported in part by JSPS KAKENHI (Grant Number JP16H06510 (Coordination Asymmetry), JP26288022, and JP18H03913), Hokuriku Bank Foundation, The Kyoto Technoscience Center, Kanazawa University CHOZEN Project, and the World Premier International Research Initiative (WPI), MEXT, Japan.

REFERENCES (1) (a) Kaifer, A. E. Interplay between Molecular Recognition and Redox Chemistry. Acc. Chem. Res. 1999, 32, 62-71. (b) Beer, P. D.; Gale, P. A. Anion Recognition and Sensing: The State of the Art and Future Perspectives. Angew. Chem. Int. Ed. 2001, 40, 486-516. (c) Dsouza, R. N.; Pischel, U.; Nau, W. M. Fluorescent Dyes and Their Supramolecular Host/Guest Complexes with Macrocycles in Aqueous Solution. Chem. Rev. 2011, 111, 7941-7980.


18

Page 19 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(2) (a) Cacciapaglia, R.; van Doorn, A. R.; Mandolini, L.; Reindoudt, D. N.; Verboom, W. Differential Metal Ion Stabilization of Reactants and Transition States in the Transacylation of Crown Ether Aryl Acetates. J. Am. Chem. Soc. 1992, 114, 2611-2617. (b) Itoh, S.; Taniguchi, M.; Takada, N.; Nagatomo, S.; Kitagawa, T.; Fukuzumi, S. Effects of Metal Ions on the Electronic, Redox, and Catalytic Properties of Cofactor TTQ of Quinoprotein Amine Dehydrogenases. J. Am. Chem. Soc. 2000, 122, 12087-12097. (c) Tsuda, A.; Fukumoto, C.; Oshima, T. Self-Activated Supramolecular Reactions: Effects of Host-Guest Recognition on the Kinetics of the Diels-Alder Reaction of Open-Chain Oligoether Quinones with Cyclopentadiene. J. Am. Chem. Soc. 2003, 125, 5811-5822. (3) (a) Monflier, E.; Fremy, G.; Castanet, Y.; Mortreux, A. Molecular Recognition between Chemically Modified β-Cyclodextrin and Dec-1-ene: New Prospects for Biphasic Hydroformylation of Water-Insoluble Olefins. Angew. Chem. Int. Ed. Engl. 1995, 34, 22692271. (b) Molenveld, P.; Engbersen, J. F. J.; Kooijman, H.; Spek, A. L.; Reinhoudt, D. N. Efficient Catalytic Phosphate Diester Cleavage by the Synergetic Action of Two Cu(II) Centers in a Dinuclear Cis-Diaqua Cu(II) Calix[4]arene Enzyme Model. J. Am. Chem. Soc. 1998, 120, 6726-6737. (c) Breslow, R.; Schmuck, C. Goodness of Fit in Complexes between Substrates and Ribonuclease Mimics: Effects on Binding, Catalytic Rate Constants, and Regiochemistry. J. Am. Chem. Soc. 1996, 118, 6601-6605. (d) Ortega-Caballero, F.; Rousseau, C.; Christensen, B.; Petersen, T. E.; Bols, M. Remarkable Supramolecular Catalysis of Glycoside Hydrolysis by a Cyclodextrin Cyanohydrin. J. Am. Chem. Soc. 2005, 127, 3238-3239. (4) Yan, X.; Wang, F.; Zheng. B.; Huang, F. Stimuli-responsive supramolecular polymeric materials. Chem. Soc. Rev. 2012. 41, 6042-6065.


19


Page 20 of 33

(5) (a) Shinkai, S.; Ikeda, M.; Sugasaki, A.; Takeuchi, M. Positive Allosteric Systems Designed on Dynamic Supramolecular Scaffolds: Toward Switching and Amplification of Guest Affinity and Selectivity. Acc. Chem. Res. 2001, 34, 494-503. (b) Takeuchi, M.; Ikeda, M.; Sugasaki, A.; Shinkai, S. Molecular Design of Artificial Molecular and Ion Recognition Systems with Allosteric Guest Responses. Acc. Chem. Res. 2001, 34, 865-873. (c) Oliveri, C. G.; Ulmann, P. A.; Wiester, M. J.; Mirkin, C. A. Heteroligated Supramolecular Coordination Complexes Formed via the Halide-Induced Ligand Rearrangement Reaction. Acc. Chem. Res. 2008, 41, 1618-1629. (d) Nabeshima, T.; Akine, S. Functional Supramolecular Systems with Highly Cooperative and Responding Properties. Chem. Rec. 2008, 8, 240-251. (e) Isaacs, L. Stimuli Responsive Systems Constructed Using Cucurbit[n]uril-Type Molecular Containers. Acc. Chem. Res. 2014, 47, 2052-2062. (f) Zarra, S.; Wood, D. M.; Roberts, D. A.; Nitschke, J. R. Molecular containers in complex chemical systems. Chem. Soc. Rev. 2015, 44, 419-432. (6) (a) Shchori, E.; Jagur-Grodzinski, J.; Shporer, M. Kinetics of Complexation of Macrocyclic Polyethers with Sodium Ions by Nuclear Magnetic Resonance Spectroscopy. II. Solvent Effects. J. Am. Chem. Soc. 1973, 95, 3842-3846. (b) Strasser, B. O.; Popov, A. I. Influence of Solvent Properties on the Kinetics of Complexation of the Sodium Ion with 18-Crown-6. J. Am. Chem. Soc. 1985, 107, 7921-7924. (c) Liesegang, G. W.; Farrow, M. M.; Vazquez, F. A.; Purdie, N.; Eyring, E. M. Ultrasonic Absorption Kinetic Studies of the Complexation of Aqueous Li+, Na+, Rb+, Tl+, Ag+, NH4+, and Ca2+ by 18-Crown-6. J. Am. Chem. Soc. 1977, 99, 3240-3243. (7) (a) Palmer, L. C.; Rebek, Jr., J. The ins and outs of molecular encapsulation. Org. Biomol. Chem. 2004, 2, 3051-3059. (b) Pluth, M. D.; Raymond, K. N. Reversible guest exchange


20

Page 21 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mechanisms in supramolecular host-guest assemblies. Chem. Soc. Rev. 2007, 36, 161-171. (c) Rieth, S.; Hermann, K.; Wang, B.-Y.; Badjíc, J. D. Controlling the dynamics of molecular encapsulation and gating. Chem. Soc. Rev. 2011, 40, 1609-1622. (8) (a) Koshland, D. E. Application of a theory of enzyme specificity to protein synthesis. Proc. Natl. Acad. Sci. U. S. A. 1958, 44, 98-104. (b) Davis, A. M.; Teague, S. J. Hydrogen Bonding, Hydrophobic Interactions, and Failure of the Rigid Receptor Hypothesis. Angew. Chem. Int. Ed. 1999, 38, 736-749. (c) Williamson, J. R. Induced fit in RNA-protein recognition. Nat. Struct. Biol. 2000, 7, 834-837. (d) Leulliot, N.; Varani, G. Current Topics in RNA-Protein Recognition: Control of Specificity and Biological Function through Induced Fit and Conformational Capture. Biochemistry 2001, 40, 7947-7956. (e) Sherman, W.; Beard, H. S.; Farid, R. Use of an Induced Fit Receptor Structure in Virtual Screening. Chem. Biol. Drug Des. 2006, 67, 83-84. (f) Alonso, H.; Bliznyuk, A. A.; Gready, J. E. Combining Docking and Molecular Dynamic Simulations in Drug Design. Med. Res. Rev. 2006, 26, 531-568. (g) Zaher, H. S.; Green, R. Fidelity at the Molecular Level: Lessons from Protein Synthesis. Cell 2009, 136, 746-762. (h) Mittag, T.; Kay, L. E.; Forman-Kay, J. D. Protein dynamics and conformational disorder in molecular recognition. J. Mol. Recognit. 2010, 23, 105-116. (9) (a) Fujita, M.; Ogura, K. Transition-metal-directed assembly of well-defined organic architectures possessing large voids: from macrocycles to [2]catenanes. Coord. Chem. Rev. 1996, 148, 249-264. (b) Piguet, C.; Bünzli, J.-C. G. Mono- and polymetallic lanthanidecontaining functional assemblies: a field between tradition and novelty. Chem. Soc. Rev. 1999, 28, 347-358. (c) Molenveld, P.; Engbersen J. F. J.; Reinhoudt, D. N. Dinuclear metallophosphodiesterase models: application of calix[4]arenes as molecular scaffolds. Chem. Soc. Rev. 2000, 29, 75-86. (d) Ueno, A.; Moriwaki, F.; Osa, T.; Hamada, F.; Murai, K.


21


Page 22 of 33

Association, Photodimerization, and Induced-Fit Types of Host-Guest Complexation of Anthracene-Appended -Cyclodextrin Derivatives. J. Am. Chem. Soc. 1988, 110, 43234328. (e) Anderson, H. L.; Hunter, C. A.; Meah, M. N.; Sanders, J. K. M. Thermodynamics of Induced-Fit Binding Inside Polymacrocyclic Porphyrin Hosts. J. Am. Chem. Soc. 1990, 112, 5780-5789. (f) Haino, T.; Rudkevich, D. M.; Shivanyuk, A.; Rissanen, K.; Rebek, Jr., J. Induced-Fit Molecular Recognition with Water-Soluble Cavitands. Chem. Eur. J. 2000, 6, 3797-3805. (g) Chang, C.-E.; Gilson, M. K. Free Energy, Entropy, and Induced Fit in HostGuest Recognition: Calculations with the Second-Generation Mining Minima Algorithm. J. Am. Chem. Soc. 2004, 126, 13156-13164. (h) Le Gac, S.; Marrot, J.; Reinaud, O.; Jabin, I. Allosterically Coupled Double Induced Fit for 1+1+1+1 Self-Assembly of a Calix[6]trisamine, a Calix[6]trisacid, and Their Guests. Angew. Chem. Int. Ed. 2006, 45, 3123-3126. (i) Taratula, O.; Hill, P. A.; Khan, N. S.; Carroll, P. J.; Dmochowski, I. J. Crystallographic observation of 'induced fit' in a cryptophane host–guest model system. Nat. Commun. 2010, 1, 148. (j) Albrecht, M.; Isaak, E.; Baumert, M.; Gossen, V.; Raabe, G.; Fröhlich, R. “Induced Fit” in Chiral Recognition: Epimerization upon Dimerization in the Hierarchical Self-Assembly of Helicate-type Titanium(IV) Complexes. Angew. Chem. Int. Ed. 2011, 50, 2850-2853. (k) Juríček, M.; Strutt, N. L.; Barnes, J. C.; Butterfield, A. M.; Dale, E. J.; Baldridge, K. K.; Stoddart, J. F.; Siegel, J. S. Induced-fit catalysis of corannulene bowl-to-bowl inversion. Nat. Chem. 2014, 6, 222-228. (10) (a) Monod, J.; Wyman, J.; Changeux, J.-P. On the Nature of Allosteric Transitions: A Plausible Model. J. Mol. Biol. 1965, 12, 88-118. (b) James, L. C.; Tawfik, D. S. Conformational diversity and protein evolution - a 60-year-old hypothesis revisited. Trends Biochem. Sci. 2003, 28, 361-368. (c) Boehr, D. D.; Wright, P. E. How Do Proteins Interact?


22

Page 23 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Science 2008, 320, 1429-1430. (d) Boehr, D. D.; Nussinov, R.; Wright, P. E. The role of dynamic conformational ensembles in biomolecular recognition. Nat. Chem. Biol. 2009, 5, 789-796. (e) Csermely, P.; Palotai, R.; Nussinov, R. Induced fit, conformational selection and independent dynamic segments: an extended view of binding events. Trends Biochem. Sci. 2010, 35, 539-546. (f) Haller, A.; Soulière, M. F.; Micura, R. The Dynamic Nature of RNA as Key to Understanding Riboswitch Mechanisms. Acc. Chem. Res. 2011, 44, 13391348. (g) Stank, A.; Kokh, D. B.; Fuller, J. C.; Wade, R. C. Protein Binding Pocket Dynamics. Acc. Chem. Res. 2016, 49, 809-815. (11) Most of guest binding phenomena with conformational changes are interpreted as inducedfit, see: (a) Fujita, M.; Nagao, S.; Ogura, K. Guest-Induced Organization of a ThreeDimensional Palladium(II) Cagelike Complex. A Prototype for “Induced-Fit” Molecular Recognition. J. Am. Chem. Soc. 1995, 117, 1649-1650. (b) Corbett, P. T.; Tong, L. H.; Sanders, J. K. M.; Otto, S. Diastereoselective Amplification of an Induced-Fit Receptor from a Dynamic Combinatorial Library. J. Am. Chem. Soc. 2005, 127, 8902-8903. (c) Hiraoka, S.; Harano, K.; Nakamura, T.; Shiro, M.; Shionoya, M. Induced-Fit Formation of a Tetrameric Organic Capsule Consisting of Hexagram-Shaped Amphiphile Molecules. Angew. Chem. Int. Ed. 2009, 48, 7006-7009. (d) Riddell, I. A.; Smulders, M. M. J.; Clegg, J. K.; Hristova, Y. R.; Breiner, B.; Thoburn, J. D.; Nitschke, J. R. Anion-induced reconstitution of a selfassembling system to express a chloride-binding Co10L15 pentagonal prism. Nat. Chem. 2012, 4, 751-756. (e) Akine, S.; Kusama, D.; Nabeshima, T. Conformational control of electronrich calix[6]arene skeleton by paraquat recognition. Tetrahedron Lett. 2013, 54, 205-209. (f) Rizzuto, F. J.; Nitschke, J. R. Stereochemical plasticity modulates cooperative binding in a CoII12L6 cuboctahedron. Nat. Chem. 2017, 9, 903-908. (g) Zhang, T.; Zhou, L.-P.; Guo, X.-


23


Page 24 of 33

Q.; Cai, L.-X.; Sun, Q.-F. Adaptive self-assembly and induced-fit transformations of anionbinding metal-organic macrocycles. Nat. Commun. 2017, 8, 15898. (12) (a) Tummino, P. J.; Copeland, R. A. Residence Time of Receptor-Ligand Complexes and Its Effect on Biological Function. Biochemistry 2008, 47, 5481-5492. (b) Hammes, G. G.; Chang, Y.-C; Oas, T. G. Conformational selection or induced fit: A flux description of reaction mechanism. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 13737-13741. (c) Bae, S.; Kim, D.; Kim, K. K.; Kim, Y.-G.; Hohng, S. Intrinsic Z-DNA Is Stabilized by the Conformational Selection Mechanism of Z-DNA-Binding Proteins. J. Am. Chem. Soc. 2011, 133, 668-671. (d) Vogt, A. D.; Cera, E. D. Conformational Selection or Induced Fit? A Critical Appraisal of the Kinetic Mechanism. Biochemistry 2012, 51, 5894-5902. (e) Kim. E.; Lee, S.; Jeon, A.; Choi, J. M.; Lee, H.-S. Hohng, S.; Kim, H.-S. A single-molecule dissection of ligand binding to a protein with intrinsic dynamics. Nat. Chem. Biol. 2013, 9, 313-318. (f) Suddala, K. C.; Wang, J.; Hou, Q.; Walter, N. G. Mg2+ Shifts Ligand-Mediated Folding of a Riboswitch from Induced-Fit to Conformational Selection. J. Am. Chem. Soc. 2015, 137, 14075-14083. (g) Gouridis, G.; Schuurman-Wolters, G. K.; Ploetz, E.; Husada, F.; Vietrov, R.; de Boer, M.; Cordes, T.; Poolman, B. Conformational dynamics in substratebinding domains influences transport in the ABC importer GlnPQ. Nat. Struct. Mol. Biol. 2015, 22, 57-64. (13) Differentiation of induced-fit and conformational selection in artificial systems, see: Hong, C. M.; Kaphan, D. M.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. Conformational Selection as the Mechanism of Guest Binding in a Flexible Supramolecular Host. J. Am. Chem. Soc. 2017, 139, 8013-8021.


24

Page 25 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(14) (a) Boulas, P. L.; Gómez-Kaifer, M.; Echegoyen, L. Electrochemistry of Supramolecular Systems. Angew. Chem. Int. Ed. 1988, 37, 216-247. (b) Matsue, T.; Evans, D. H.; Osa, T.; Kobayashi, N. Electron-Transfer Reactions Associated with Host-Guest Complexation. Oxidation of Ferrocenecarboxylic Acid in the Presence of -Cyclodextrin. J. Am. Chem. Soc. 1985, 107, 3411-3417. (c) Beer, P. D.; Blackburn, C.; McAleer, J. F.; Sikanyika, H. RedoxResponsive Crown Ethers Containing a Conjugated Link between the Ferrocene Moiety and a Benzo Crown Ether. Inorg. Chem. 1990, 29, 378-381. (d) Hansen, T. K.; Jørgensen, T.; Stein, P. C.; Becher, J. Crown Ether Derivatives of Tetrathiafulvalene. 1. J. Org. Chem. 1992, 57, 6403-6409. (e) Wang, Y.; Mendoza, S.; Kaifer, A. E. Electrochemical Reduction of Cobaltocenium in the Presence of -Cyclodextrin. Inorg. Chem. 1998, 37, 317-320. (15) Richens, D. T. Ligand Substitution Reactions at Inorganic Centers. Chem. Rev. 2005, 105, 1961-2002. (16) Sakata, Y.; Murata, C.; Akine, S. Anion-capped metallohost allows extremely slow guest uptake and on-demand acceleration of guest exchange. Nat. Commun. 2017, 8, 16005. (17) (a) Akine, S.; Utsuno, F.; Nabeshima, T. Highly efficient regulation of cation recognition and promotion of self-assembly by metalation of a macrocyclic bis(N2O2) ligand with nickel(II). Chem. Commun. 2010, 46, 1029-1031. (b) Akine, S.; Utsuno, F.; Piao, S.; Orita, H.; Tsuzuki, S.; Nabeshima, T. Synthesis, Ion Recognition Ability, and Metal-Assisted Aggregation Behavior of Dinuclear Metallohosts Having a Bis(Saloph) Macrocyclic Ligand. Inorg. Chem. 2016, 55, 810-821.


25


Page 26 of 33

TOC Graphic


26

Page 27 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1. (a) Schematic illustration of two distinct mechanisms, recognition first and reaction first, in host– guest binding. (b) Design of macrocyclic host [LCo2(pip)4]2+ with reactive sites. 170x70mm (300 x 300 DPI)



Figure 2. Crystal structures of (a) [LCo2(pip)4](OTf)2 with thermal ellipsoids plotted at the 50% probability level, (b) [LCo2(pip)2(OMe)2•Na(MeOH)2](OTf) with thermal ellipsoids plotted at the 30% probability level, and (c) [LCo2(pip)2(OMe)2•K(MeOH)2](OTf) with thermal ellipsoids plotted at the 30% probability level. Hydrogen atoms, solvent molecules, and triflate anions are omitted for clarity. 84x155mm (300 x 300 DPI)


Page 28 of 33

Page 29 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. (a) 1H NMR spectral change of [LCo2(pip)4](OTf)2 in CD3OD after the addition of 1 equiv of NaOTf. See Figure 1b for signal assignments. (b) The scheme of axial ligand exchange of [LCo2(pip)4]2+ in methanol in the presence of NaOTf. There are two possible pathways during the formation of [LCo2(pip)3(OMe)•Na]2+ depending on whether Na+ recognition or ligand exchange occurs first. 120x150mm (300 x 300 DPI)



Figure 4. Time-course analysis of ligand exchange of piperidine with methoxo ligands in [LCo2(pip)4]2+ in the absence/presence of NaOTf. (a) Reaction scheme of the axial ligand exchange in [LCo2(pip)4]2+ in methanol in the absence of NaOTf. (b) 1H NMR spectral changes (imine proton) in the absence of NaOTf (blue diamonds, [LCo2(pip)4]2+; red squares, [LCo2(pip)3(OMe)]+; green triangles, [LCo2(pip)2(OMe)2]). (c) Plots of mole fractions of the three components versus time after dissolution in CD3OD in the absence of NaOTf. (d) Reaction scheme of the axial ligand exchange of [LCo2(pip)4]2+ in methanol in the presence of NaOTf. (e) 1H NMR spectral changes (imine proton) in the presence of 10 equiv of NaOTf (blue diamonds, [LCo2(pip)4]2+; red squares, [LCo2(pip)3(OMe)•Na]2+; green triangles, [LCo2(pip)2(OMe)2•Na]+). (f) Plots of mole fractions of the three components versus time after dissolution in CD3OD in the presence of NaOTf. 178x71mm (300 x 300 DPI)


Page 30 of 33

Page 31 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 5. Na+ concentration dependence of the kinetic parameters of the Na+ recognition process by [LCo2(pip)4]2+. (a) Plots of k1obs versus the equivalent of Na+. (b) Plots of k2obs versus the equivalent of Na+. 85x43mm (300 x 300 DPI)



Figure 6. Switching of the mechanisms, recognition first versus reaction first, depending on the guest cations and their amount. 81x82mm (300 x 300 DPI)


Page 32 of 33

Page 33 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Graphical abstract 82x44mm (300 x 300 DPI)


Switching of recognition first and reaction first mechanisms in

Recommend Documents