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1 Electronic Supplementary Material (ESI) for Chemical Science. This journal is The Royal Society of Chemistry 2016 Supporting Information Coevolution and metry in covalent dynamic systems Sébastien Dhers, Jan Holub and Jean-Marie Lehn Laboratoire de Chimie Supramoléculaire, ISIS, Université de Strasbourg, 8 Allée Gaspard Monge, Strasbourg, France. lehn@unistra.fr Instrumentation: NMR spectra were recorded on Bruker Advance 400 ( MHz for 1 H and MHz for 13 C), Bruker Advance III plus 400 ( MHz for 1 H and MHz for 13 C), and Bruker Advance III 600 ( MHz for 1 H and MHz for 13 C) NMR spectrometers. All the collected spectra were referenced on residual solvent signal according to Nudelman and coworkers. [1] Mass spectra were obtained on Bruker MicroTOF and HRMS on Bruker MicroTOF- Q, both with electrospray ionization. Nominal precision of the HRMS analysis is 10 ppm. Deuterated solvents were purchased from Euriso-TOP and used without further purification. Solvents and reagents were purchased from Sigma-Aldrich, Alfa Aesar, and STREM and were used without further purification. Experimental part I: Agonistic coevolution of a dynamic system under effector competition All reagents were purchased from commercial sources and used without further purification. All compounds were prepared as described and all NMR spectra of isolated complexes Zn.1- Me.N2C3, Zn.1-Me.N2C4, Hg.1-Me.N2C3 and Hg.1-Me.N2C4 are reported in the literature. [2] All NMR spectra were recorded in a CDCl 3 /CD 3 CN (1:1) mixture using a Bruker Advance III plus 400 MHz, with the CH 3 CN peak chosen for calibn. NMR solvents were filtered as received through a pad of Al 2 O 3 and subsequently stored over freshly activated molecular sieves under exclusion of light. Ratio of Zn(II) and Hg(II) complexes have been determined by 1 H NMR integn (error on % determination lower than 5%). 13 C and 2D S1

2 NMR experiments are shown in the ESI. NMR spectra are reported thereafter with a color code: in blue are characteristic peaks of N2C3 complexes, in green are characteristic peaks of N2C4 complexes, and in black are overlapping peaks from both complexes. Integns are reported relative to each complex individually, in order to simplify the notation. Competition experiment (1). Anhydrous Zn(OTf) 2 (50 µl in 60mM solution in CDCl 3 */CD 3 CN: 1/1, 3 µmoles) was added to a 5 mm solution of 1-Me (0.805 mg, 3 µmoles) in CDCl 3 */CD 3 CN: 1/1 (0.6 ml). 1,3-diaminopropane, N2C3, and 1,4-diaminobutane, N2C4, (for each, 50 µl in 60mM solution in CDCl 3 */CD 3 CN: 1/1, 3 µmoles) were then added. Thermodynamic equilibrium was reached after 1 day at 60 C. 1 H NMR (400 MHz, CDCl 3 */CD 3 CN: 1/1): 8.59 (s, 1H), 8.54 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.23 (m, J = 8.0, 2H), 8.09 (t, J = 8.0, 2H), 8.00 (s, 2H), 7.84 (d, J = 7.6, 2H), 7.78 (d, J = 7.6, 2H), 7.46 (d, J = 8.4, 2H), 7.40 (d, J = 6.8, 2H), (m, 8H), 3.64 (s, 6H), 2.04 (m, 8H). Competition experiment (2). Anhydrous Hg(OTf) 2 (50 µl in 60mM solution in CDCl 3 */CD 3 CN: 1/1, 3 µmoles) was added to a 5 mm solution of 1-Me (0.805 mg, 3 µmoles) in CDCl 3 */CD 3 CN: 1/1 (0.6 ml). 1,3-diaminopropane, N2C3, and 1,4-diaminobutane, N2C4, (for each, 50 µl in 60mM solution in CDCl 3 */CD 3 CN: 1/1, 3 µmoles) were then added. Thermodynamic equilibrium was reached after 2 days at 60 C. 1 H NMR (400 MHz, CDCl 3 */CD 3 CN: 1/1): 8.81 (t, 1H, 1H-199Hg J = 79.6 Hz), 8.80 (t, 1H, 1H-199Hg J = Hz), 8.76 (t, 1H, 1H-199Hg J = 83.2 Hz), 8.70 (t, 1H, 1H-199Hg J = Hz), 8.32 (t, J = 8.0, 2H), 8.16 (m, 2H), 8.08 (s, 2H), 7.99 (dd, J = 8.0, J = 1.0, 2H), 7.90 (dd, J = 8.0, J = 1.0, 2H), 7.66 (d, J = 8.4, 2H), 7.51 (m, 2H), 4.20 (m, 8H), 3.68 (s, 6H), (m, 8H). Competition experiment (3). Anhydrous Zn(OTf) 2 and Hg(OTf) 2 (each 50 µl in 60mM solution in CDCl 3 */CD 3 CN: 1/1, 3 µmoles) was added to a 5 mm solution of 1-Me (0.805 mg, 3 µmoles) in CDCl 3 */CD 3 CN: 1/1 (0.6 ml). 1,3-diaminopropane, N2C3, and 1,4- diaminobutane, N2C4, (for each, 50 µl in 60mM solution in CDCl 3 */CD 3 CN: 1/1, 3 µmoles) were then added. Thermodynamic equilibrium was reached after 3 days at 60 C. 1 H NMR (400 MHz, CDCl 3 */CD 3 CN: 1/1): ): 8.81 (t, 1H, 1H-199Hg J = 79.6 Hz), 8.80 (t, 1H, 1H-199Hg J = Hz), 8.56 (s, 1H), 8.46 (s, 1H), 8.32 (t, J=8.0, 1H), 8.23 (m, J = 8.0, 1H), 8.14 (m, 1H), 8.09 (m, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.99 (m, 1H), 7.90 (m, 1H), 7.85 (d, J = 7.6, 1H), 7.79 (d, J = 7.6, 1H), 7.64 (d, J = 8.4, 1H), 7.51 (m, 1H), 7.46 (d, J = 8.4, 1H), 7.40 (d, J = 6.8, 1H), 4.2 (m, 8H), 3.66 (s, 6H), (m, 8H). S2

3 Figure S1. Zoom on the 1 H NMR spectrum of competition experiment (2) showing 1 H- 199 Hg coupling. Blue and green represent Hg.1-Me.N2C3 complex and Hg.1-Me.N2C4 complex, respectively. Figure S2. Summary of competition experiments (4) and (5). S3

4 Figure S3. 1 H NMR spectrum of competition experiment (4) between the components 1-Me (1eq.), N2C3 (1eq.) and in presence of (top) 1eq. of Zn(OTf) 2, (middle) 1eq. of Hg(OTf) 2 and of (bottom) both Hg(OTf) 2 and Zn(OTf) 2 with 1eq. each. Figure S4. 1 H NMR spectrum of competition experiment (5) between the components 1-Me (1eq.), N2C4 (1eq.) and in presence of (top) 1eq. of Zn(OTf) 2, (middle) 1eq. of Hg(OTf) 2 and of (bottom) both Hg(OTf) 2 and Zn(OTf) 2 with 1eq. each. S4

5 Experimental part II: Agonistic/Antagonistic competitive coevolution and dynamic metry in a DCL Component 6-Phenylpyridine-2-carbaldehyde (A) was prepared according the literature. 3,4 Components 4-chlorobenzaldehyde (A ), benzhydrazide (B) and p-toluidine (4-methylanilin, B ) were purchased from Sigma-Aldrich, Alfa Aesar, and STREM and were used without further purification. Constituents AB, AB,, were prepared according the general procedure for imine and hydrazone formation and together with Zn(AB) 2 and Cu(AB ) 2 are described in the reference [4]. All the below described systems were obtained by mixing in advance prepared solutions of known concentn of individual components (A, A, B, B ) in CD 3 CN. General method for prepan of imines and acylhydrazones 1.05 eq. of aldehyde and 1 eq. of amine or acylhydrazide were weighted in a round bottom flask equipped with a stirrer. After addition of ethanol, the mixture was heated to reflux overnight. Analytically clean product precipitated from the reaction mixture upon cooling. When the product did not precipitate upon cooling, ethanol was evaporated, petroleum ether was added and the solution was sonicated until the desired product precipitated. If needed, a recrystallization from ethanol was done to purify obtained constituents. Equilibn of the library A, A, B, B in absence and presence of Cu(I) or Zn(II).* *For reference only. For detailed description of the spectra and basic evolution of the system see reference [4]. All the transformations were tested starting from either the mixture of components, the preequilibrated mixture of components and the mixture of agonists (AB+ or AB +). Regardless of the path, the results were approximately the same in all cases. All the values here are average values obtained from at least three distinct experiments. S5

6 Z-AB A AB B Figure S5. Equilibrated mixture of A, A, B and B. A portion of the 400 MHz 1 H NMR spectrum of an equilibrated mixture of components A, A, B and B in absence of any metal cation after 12 h at 60 C: Four constituents AB, AB, and were obtained with a distribution of 35/12/16/23 % respectively together with 14 % hydrolysis. The values were obtained as an average of three experiments with about ±2 % error. A Zn(AB) 2 Zn(AB) 2 B Figure S6. Training of the library of A, A, B and B on Zn(II). A portion of the 400 MHz 1 H NMR spectrum of the equilibrium in the presence of Zn(II). The mixture of components A, A, B and B was equillibrated in presence of 0.5 eq. Zn(OTf) 2 at 60 C for 3 h. The resulting distribution is Zn(AB) 2 /AB // /hydrolysis = 50/<1/<1/36/12. The values were obtained as an average of three experiments with about ±2 % error. S6

7 Cu(AB ) 2 Cu(AB ) 2 A Z-AB B Figure S7. Training of the library of A, A, B and B on Cu(I). A portion of the 400 MHz 1 H NMR spectrum of the mixture of components A, A, B and B equilibrated in presence of 0.5 eq. of Cu(I)OTf at 60 C for 12 h. The resulting distribution is AB/Cu(AB ) 2 // /hydrolysis = 10/31/32/18/9. The values were obtained as an average of three experiments with about ±2% error. Constitutional Dynamic Ratiometry experiments: A series of samples was prepared in which the amount of Cu(I) gradually decreased from 0.5 eq. to 0 eq. (in respect to A) and the amount of Zn(II) correspondingly increased from 0 eq. to 0.5 eq. All components (A, A, B, B ) including metal cations in appropriate s (acu(i) and bzn(ii), a + b = 1/2xA) were heated at 60 C for 12 h to achieve thermodynamic equilibn. In the resulting mixtures, the of antagonists AB and AB was calculated from the signal integn of all species (free, bound in complex, E and Z isomer) of a given constituent. (Figure 2 and S8). The observed co-evolution originates from the differential amplification effects of these two effectors on the antagonists AB and AB, both containing the aldehyde A, and their direct competition for this constituents (in order to form their respective complexes). Therefore, increasing the of Zn(II) in the Cu(I)/Zn(II) mixture amplifies proportionally the formation of AB. This correlation is shown on the graph in Figure S8, further illustrating the concept of coevolution. From the graph in Figure S8 it is possible to directly relate the of antagonists to the of the metals (Cu/Zn) present, hence to use this system as a way to analyze a mixture of S7

8 the metal cations by measuring the of constituents. In a view of the dynamic component exchange between the cation sensors AB and AB, the behavior observed can be described as constitutional dynamic metry. This is in reference to the analytical method called metry where an effector produces a different effect on two sensors, usually displayed as a change in a given macroscopic observable (like an optical effect). Two significant points can be seen in the graph: the 0.7:0.3 Cu/Zn which gives a 1:1 of AB and AB (25 % each) and the 0.5:0.5 Cu/Zn giving a 0.33:0.17 AB/AB (Figure S8). These values are in agreement with the stronger amplification caused by the Zn(II) observed during previous studies of the system. 4 The individual percentages in Figure S8 were obtained from the 1 H NMR spectra as a sum of integrals of all species belonging to particular constituent. The values reported in the graph are an average of three individual experimental values (Table S1). There is a clearly visible agonist/antagonist relationship between AB/ and /AB. The agonist pair follows in both cases the same trend while antagonist pairs have a negative correlation. It is obvious that the correlation for (light blue) and hydrolysis (pink) is somewhat variable compared to that for other constituents, and this is ascribed to its higher sensitivity to the environment, therefore its amount fluctuates more than others. It is also important to note that hydrolysis in this system under all circumstances almost exclusively concern components A and B, thus being the natural counter partners of. Indeed, if the values for hydrolysis and are summed, the resulting correlation is in nice agreement with the expected trend and gives a direct positive correlation with its agonist constituent AB. At this point it is important to note that this approach requires stoichiometric s between components of the mixture in order to obtain a linear response. S8

9 Figure S8. 1 H NMR spectra of the solutions corresponding to the metry experiments performed by addition of mixtures of Cu(I) and Zn(II) cations to the DCL of constituents AB,, AB and. All systems were formed from equimolar mixture of A, A, B, B (1.25x10-5 mol, 25 mm) with addition of a mixture of Cu(I) and Zn(II). The of Cu(I) decreases from 0.5 eq. (in respect to A, bottom spectrum) for 10 % for each spectrum (0.45, eq.) to 0 eq. (top spectrum). The of Zn(II) increases from 0 eq. (bottom spectrum) for 10 % for each spectrum to spectrum (0.05, eq.) to 0.5 eq. (in respect to A, top spectrum). Figure S9. Graph representing the evolution of the relative amounts of all constituents AB,, AB and against the Cu(I)/Zn(II). The values were obtained as an average of three experiments with about ±2 % error. See Table S1. S9

10 Table S1. Results of the metry experiments for each constituent (AB,, AB, ), obtained from integn of imines and significant peaks from 1 H NMR, with an overall 0.5 eq. of metal (Cu(I) or Zn(II)). The values were obtained as an average of three experiments with about ±2 % error. AB Cu Zn Exp.:1 Exp.:2 Exp.:3 Average Cu Zn Exp.:1 Exp.:2 Exp.:3 Average Hydrolysis (A +B ) Cu Zn Exp.:1 Exp.:2 Exp.:3 Average Overal of A +B (hydrolysis + ) S10

11 AB Cu Zn Exp.:1 Exp.:2 Exp.:3 Average Cu Zn Exp.:1 Exp.:2 Exp.:3 Average Coevolution: Synergism of pairs of agonists in a balanced full network (A) Cu(AB ) 2 (B) AB (C) (D) Zn(AB) 2 (E) E+Z-AB B (F) Figure S10. 1 H NMR (CD 3 CN) spectra of the: (A) Cu(AB ) 2 ; (B) AB ; (C) A mixture of A + B + B eq. Cu(I) eq. Zn(II) after 12 h at 60 C; (D) A mixture of A + B + B eq. Zn(II) after 12 h at 60 C; (E) A mixture of A + B + B eq. Cu(I) after 12 h at 60 C; (F) A mixture of A + B + B + 12 h, 60 C; Spectra show no formation of AB or its complex even in the presence of Cu(I). For the exact s see Table S2. S11

12 Cu(AB ) 2 Z-AB A Z-AB B Figure S11. 1 H NMR (CD 3 CN) spectra of the 2A:B:B (2:1:1) equilibrated in a presence of 0.5 eq. of Cu(I) cation (12 h, 60 C); AB and AB form in approximately 1:1. See Table S2. Table S2. Distribution of individual constituents from 1 H NMR (CD 3 CN) spectra of the A:B:B (2:1:1) equilibrated in a presence of 0.5 eq. of Cu(I) cation; AB and AB form in 1:1. Error ±2 %. AB-E AB-Z AB A B A+B+B (F) A+B+B +Cu (E) A+B+B +Zn (D) A+B+B +Cu+Zn (C) A+B+B (Fig. S11) Cascade transformations within the CDN Importance of all components: To prove the importance of all four components (A, A, B, B ) for the coevolution of the system we carried out a series of transformations in which we studied influence of particular component on the equilibrium within the CDN. All the below described transformations were done in one NMR tube in CD 3 CN as a solvent. The transformation started from the preformed constituent AB (CD 3 CN, 1.25x10-5 mol, 25 mm, (A) in Figure S12) to which 0.5 eq. of Cu(OTf) (CD 3 CN, 0.63x10-5 mol, 12.5 mm) was added to quantitatively form complex Cu(AB ) 2 ((B) in Figure S12). The following addition of 1 eq. of the component B (benzhydrazide, CD 3 CN, 1.25x10-5 mol) to the Cu(AB ) 2 then resulted in a complete disappearance of the signals of this complex ((C) S12

13 in Figure S12), instead a strong presence of the free B (p-toluidine) component as well as a strong presence of the E/Z-AB constituent (AB/AB /B = 46/2/52 %) could be observed in the 1 H NMR spectrum. The plausible explanation is that constituent AB is formed through the exchange reaction from the preformed AB in spite of the presence/complexation of the Cu(I) which as a template should stabilize imine. From this result it can be concluded, that the stability of the acylhydrazone bond (AB) is not only higher than imine bond (AB ) but it is also higher than the stability of imine complex with Cu(I) (Cu(AB ) 2 ) and therefore the formation of acylhydrazone is still thermodynamically favored. When 1 eq. of the component A (4-chlorobenzaldehyde, CD 3 CN, 1.25x10-5 mol) is added to the above described mixture, the spectrum ((D) in Figure S12) shows restored presence of the imine complex Cu(AB ) 2 as well as formation of its agonistic acylhydrazone constituent. The distribution of all four constituents in the mixture (AB/ /AB //Hydrolysis = 17/14/31/28/10 %) is in the agreement with above described coevolution experiment as well as with previously described distribution in the reference [4]. From above described evolution of the CDN it is possible to conclude that in order to induce pronounced amplification of the right agonists pair in the case of Cu(I), the presence of the noncomplexing acylhydrazone is key to counter-balance the strong preference of the network for the antagonistic acylhydrazone AB. The resulting amplification of AB / agonists pair is then result of the concerted efforts of AB templated by Cu(I) and formation of the. This experiment nicely illustrates the need of all four components as well as importance of the energetically balanced agonists pairs for the construction of the multi responsive dynamic systems/networks. Table S3. Distribution of individual constituents from 1 H NMR (CD 3 CN) spectra of the cascade reactions using A, A, B, and B. Error ±2 %. AB(E+Z) AB B A) B) C) D) (Hydr.) S13

14 D) AB +B+A + Cu(I) +24 h, 60 C A C) AB + B + Cu(I) +24 h, 60 C AB+AB Z-AB B Cu(AB ) 2 B) AB +Cu(I) +Cu(I) A) AB - metal free Figure S12. Proving the importance of all four components (A, A, B, B ) for the coevolution of the system. A) A slice of 1 H NMR spectrum of the preformed constituent AB (CD 3 CN, 1.25x10-5 mol, 25 mm); B) A slice of 1 H NMR spectrum of the same component after addition of 0.5 eq. of Cu(OTf) (CD 3 CN, 0.63x10-5 mol).; C) A slice of 1 H NMR spectrum of the Cu(AB ) 2 (spectrum B) after addition of 1 eq. of the component B (benzhydrazide, CD 3 CN, 1.25x10-5 mol) and equilibn for 24 h at the 60 C. D) A slice of 1 H NMR spectrum of the previous mixture (Z/, B, Cu(I), spectrum C) after addition of 1 eq. of the component A (4-chlorobenzaldehyde, CD 3 CN, 1.25x10-5 mol) and equilibn for 24 h at the 60 C. For the distribution see Table S3. References [1] Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, [2] (a) Ulrich, S.; Buhler, E.; Lehn, J.-M., New J. Chem. 2009, 33, ; (b) Ulrich, S.; Lehn, J.-M., J. Am. Chem. Soc. 2009, 131, [3] Arai, T.; Suzuki, K.; Synlett. 2009, 19, [4] Holub, J.; Vantomme, G.; Lehn, J.-M. J. Am. Chem. Soc. 2016, 138, [5] Benstead, D.J.; Hulme, A. N.; McNab, H.; Wight, P.; Synlett. 2005, 10, S14