DOI: 10.1002/chem.201501192
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& Dynamic Chemistry
Strain-Induced Reactivity in the Dynamic Covalent Chemistry of Macrocyclic Imines Lars Ratjen,[a, b, c] Ghislaine Vantomme,[a] and Jean-Marie Lehn*[a] Abstract: The displacement of molecular structures from their thermodynamically most stable state by imposition of various types of electronic and conformational constraints generates highly strained entities that tend to release the accumulated strain energy by undergoing either structural changes or chemical reactions. The latter case amounts to strain-induced reactivity (SIR) that may enforce specific chemical transformations. A particular case concerns dynamic covalent chemistry which may present SIR, whereby reversible reactions are activated by coupling to a high-energy state. We herewith describe such a dynamic covalent chemical (DCC) system involving the reversible imine formation reaction. It is based on the formation of strained macrocyclic bis-imine metal complexes in which the macrocyclic ligand is in a high energy form enforced by the coordination of the metal cation. Subsequent demetallation generates a highly strained free macrocycle that releases its accumulated strain energy by hydrolysis and reassembly into a resting state.
Introduction Chemical reactions are influenced by a variety of physical (pressure, temperature, light, etc.), and physicochemical factors, such as concentration, solubilities of reactants and products, additives, catalysts, as well as structural features of the reactants. Among the last, a factor which can markedly affect reactivity as well is strain in general and ring-strain in particular.[1] Strained molecules have an intrinsic entasis[2] (from the Greek word for tension), a driving force for chemical reactions. Without strain-induced reactivities, epoxide resins would not polymerise and aziridines would not react readily. Cyclic molecules [a] Dr. L. Ratjen, Dr. G. Vantomme, Prof. Dr. J.-M. Lehn Laboratoire de Chimie Supramol¦culaire, ISIS Universit¦ de Strasbourg 8 All¦e Gaspard Monge, 67000 Strasbourg (France) E-mail: [email protected] [b] Dr. L. Ratjen Fundaciûn Fraunhofer Chile Research Mariano Snchez Fontecilla 310, Piso 14, Las Condes, Santiago, (Chile) [c] Dr. L. Ratjen Facultad de Biologa Center for Bioinformatics and Integrative Biology (CBIB) Universidad Andres Bello, Av. Republica 239, Santiago (Chile) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201501192. Chem. Eur. J. 2015, 21, 10070 – 10081
Specifically, the metal-templated condensation of a dialdehyde with a linear diamine leads to a bis-imine [1+ +1]-macrocyclic complex in which the macrocyclic ligand is in a coordination-enforced strained conformation. Removal of the metal cation by a competing ligand yields a highly reactive [1+ +1]-macrocycle, which then undergoes hydrolysis to transient non-cyclic aminoaldehyde species, which then recondense to a strain-free [2+ +2]-macrocyclic resting state. The process can be monitored by 1H NMR spectroscopy. Energy differences between different conformational states have been evaluated by Hartree–Fock (HF) computations. One may note that the stabilisation of high-energy molecular forms by metal ion coordination followed by removal of the latter, offers a general procedure for producing out-of-equilibrium molecular states, the fate of which may then be examined, in particular when coupled to dynamic covalent chemical processes.
usually tend to release ring strain through structural deformations, such as bond-twisting, internally stabilizing their structure. The cyclohexane molecule adopts its non-planar chair and twisted-boat conformations to avoid the angle strain that would be caused by the deformation of the six sp3-hybridised carbon atoms in a planar hexagonal geometry, as already shown by Sachse at the end of the 19th century.[3] Nonbonded interactions between sterically demanding groups or between heteroatoms with lone pairs result in strain accumulation that leads to various types of deformations, notably in cyclic structures[4] and are basic features of conformational analysis.[5] Twisted amides, such as A[6] and B[7] present strainand distortion-induced reactivities markedly different from those of stereotypical amides (Figure 1).[8] The amide (peptide) bond plays a major role in nature as it connects the amino acid residues in proteins. The optimal conjugation of the nitrogen lone pair electrons with the carbonyl function in the planar amide group leads to the usual stability and lack of reactivity of amides towards nucleophiles. In the twisted amides A and B, in which the amide group is located at a bridgehead, such ideal electron delocalisation is Bredt’s rule-forbidden,[9] strongly influencing their reactivity by decreasing their stability and inertness towards nucleophilic attack.[6–8] As an example of reactivity induced by strain due to sterically demanding groups, we have recently reported that the in-
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Figure 1. Typical lone-pair/carbonyl conjugation (top) is prevented in the representative bridgehead twisted amides A[6] and B,[7] which present atypical reactivities. A strain-activated hydrazone C[10] is also shown.
troduction of two methyl groups in the hydrazone C[10] markedly enhances its reactivity towards the dynamic covalent exchange of the hydrazine component as a result of the distortion from planarity of the C=N¢N¢Me group that decreases the conjugation between the nitrogen C¢N¢Me electronic lone pair and the C=N double bond.[11] Besides activation by such steric repulsion and by angular deformation, very significant strain may be generated by the overall electronic effects due to heteroatoms. An emblematic case is that of 2,2’-bipyridine, which is about 30 kJ mol¢1 less stable in its cisoid form than in its transoid one.[12] This strong orientational effect has been implemented for the enforced generation of helically wrapped molecular strands.[13] Conversely, the binding of metal cations to these strands causes their unwrapping into the cisoid orientations of the N,N’-subunits leading to metal complexes in which the coordinated ligands adopt high-energy linear shapes stabilised by the binding energy of the metal ions. On removal of these cations from the complexes, the ligands immediately return to their much more stable helical form, providing also for the possibility to generate reversible extension/contraction molecular motions.[14] We herewith report that such strong structure-enforcing effects may be recruited towards the induction of strain-induced reactivity. Indeed, macrocyclic ligands in a highly strained state can be generated by metal-templated synthesis, whereby metal-ion complexation enforces a high-energy conformation of the ligand, the strain energy accumulated in the ligand being overcompensated by the binding energy of the metal cation(s) to the coordinating (nitrogen) heteroatoms.[15, 16] Hence, the removal of the coordinated metal ion by a superior competitive ligand may be expected to result in the formation of a highly strained free macrocycle in which the heteroatomic subunits are in an unstable orientation constrained by the cyclic structure. This is in particular the case for macrocyclic ligands incorporating coordination subunits, such as 2,2’-bipyridine (or terpyridine), as noted above. From the point of view of constitutional dynamic chemistry (CDC),[17] the generation of such highly strained entities by demetallation opens up very interesting possibilities towards the activation of constitutional modification through component reorganisation and exchange processes. Chem. Eur. J. 2015, 21, 10070 – 10081
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We have previously described a system that displays combined constitutional and morphological dynamics, in which the morphological change triggered by the binding and removal of a metal ion results in a reversible constitutional interconver+1]-macrocycle and an uncomsion between a complexed [1+ plexed free ligand state that may contain the corresponding [2+ +2]-macrocycle (together with linear oligomers) (Scheme 1).[18] This process is based on the ability to switch a tridentate terpyridine-type coordination subunit reversibly between an “extended” W-shaped state and a “compact” Ushaped state through the binding and removal of a metal ion.[18c]
Scheme 1. Schematic representation of the principle of strain-induced reactivity through the generation of an out-of-equilibrium high-energy state in a dynamic covalent system. It implements constitutional switching between a “metallo-macrocycle state” (right) and an uncomplexed “resting state” (left) in response to W-U shape changes and proceeds through a strained free macrocycle (center). The overall process involves the following steps: 1) reversible switching of the ligand molecule from the free W shape to the U +1]-macrocycle forshape in the complex on cation coordination (top); 2) [1+ mation on condensation with a difunctional chain via a covalent dynamic connection (right); 3) removal of the metal cation with generation of a strain+1]-macrocycle presenting strain-induced reactivity (bottom); 4) relaxaed [1+ +2]-macrocycle tion to the thermodynamically stable state comprising the [2+ +1]-macrocycle represents and eventually some oligomers (left); 5) the [1+ a kinetically trapped out-of-equilibrium high energy state. The direction of the arrows indicates the orientation of the aldehyde functional groups in the dialdehyde compounds 1 and 2. “Metallo-macrocycle state” and “resting +1]-macrocycle and the unstate” designate respectively the complexed [1+ complexed relaxed product(s), the [2+ +2]-macrocycle, eventually together with linear oligo(poly)mers depending on the diamine.
The structures of the molecules and metal complexes investigated herein are represented in Figure 2. Thus, the dialdehyde 1 in its preferred W-shaped form undergoes polycondensation with a diamine to give a [2+ +2]-macrocycle (e.g. 12·(N2O)2) and/or linear oligo(poly)mers, depending on the diamine.[18] The binding of a metal ion to 1 results in switching the W-shaped core into a U-shaped one in which the dialdehyde functions are held in an orientation favouring the formation of a macrocycle on reaction with a suitable diamine, as exemplified by structure Cd·(1·N2O) (Figure 2). A similar behaviour is presented by the bis-imines formed by pyridine-2,6-di-
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Figure 2. Structures of the molecules and metal complexes considered herein. Note that the bis-imine subunits in the free macrocyclic ligands 12·(N2O)2 and 22·(N2O3)2 are represented in their energetically preferred conformation.
carboxaldehyde 2 with linear diamines (Figure 2). These systems display reversible switching between macrocyclic complex and uncomplexed “free” (large macrocycle and/or oligo(poly)mer) states upon coordination of a metal ion or its removal by the addition of a competitive binder. The involved reactions (imine formation, imine exchange, complexation and decomplexation) are carried out at equilibrium condition and can be followed by 1H NMR spectroscopy. Considering the above comments, the crucial feature in the observed transformation from the macrocyclic complex to the uncomplexed products resides in the formation of a highly strained macrocyclic free ligand upon removal of the metal cation. It led us to investigate in more detail the strain-induced reactivity (SIR) resulting from the unfavourable interactions ac+1]-macrocyclic ligand structure by cumulated in the free [1+ following its fast transformation into strain-relaxed products by 1 H NMR monitoring of the transient demetallated macrocycle(s). In particularly, the expected strainless products would be [2+ +2]-macrocycle and/or linear oligo(poly)mers depending on the nature of the diamine. In the following, “free state” or “relaxed state” will be used to designate the state of the system characterised by these uncomplexed strainless products.
Results and Discussion In order to investigate the transformation undergone by the free macrocycles generated by removal of the metal cations from the corresponding macrocyclic complexes, it was first necessary to establish in separate experiments, the nature of the compounds formed by reaction of dialdehydes 1 and 2 with the diamines N2O and N2O3 in absence and in presence of metal cations.[19] Chem. Eur. J. 2015, 21, 10070 – 10081
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Reaction of dialdehyde 1 with the diamine N2O—formation +2]-macrocycle 12·(N2O)2 of the (dimeric) [2+ We explored the resting state formed between the dialdehyde 1 and the diamine N2O. Compounds 1 and N2O (1 equiv each) were dissolved in CD3CN/CDCl3 1:1 at 10 mm concentration in an NMR tube and left to equilibrate at 60 8C. This reaction mixture was then analysed by 1D- and 2D-NMR spectroscopy as well as by MS (MALDI and ESI; see Supporting Information, pp. 5–6) revealing the formation of a [2+ +2]-macrocycle 12·(N2O)2, which was fully characterised in earlier work.[18a] Also the NOESY spectral data support the relaxed W form. The solid-state structure for an analogous derivative of the dialdehyde 2 also displays a W shape.[20] Reaction of dialdehyde 1 with the diamine N2O in presence of cadmium ions—metal-templated formation of the macrocyclic complex Cd·(1·N2O). As metal cation we chose to work with cadmium instead of the previously used zinc, mercury and lead cations[18] in view of the nuclear spin of 1/2 of the 111Cd and 113Cd isotopes, resulting in the observation of proton–cadmium spin–spin coupling in the 1H NMR spectra of Cd2 + complexes.[21] A mixture of dialdehyde 1, diamine N2O and cadmium triflate (1 equiv each) dissolved in CD3CN/CDCl3 1:1 at 10 mm concentration led to the formation of the bis-imine [1+ +1]-macrocycle Cd·(1·N2O). This macrocyclic complex was characterised by 1Dand 2D-NMR spectroscopy, Cd-NMR spectroscopy as well as by MS (MALDI and ESI; see Supporting Information, pp. 15–18). The imine peaks showed a coupling pattern in which the coupling constants with the two Cd isotopes 111Cd and 113Cd differed by roughly 1 Hz (Figure 3).
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Figure 3. Illustration of the H–CdJ-coupling pattern with the two of the macrocyclic complex Cd·(1·N2O).
111
Cd and 113Cd isotopes in the 1H NMR spectrum
Interestingly, when only 0.5 equivalents of Cd(OTf)2 was used, a defined mixture of the [1+ +1]-complex Cd·(1·N2O) and the [2+ +2]-macrocycle 12·(N2O)2 was observed. The NMR signals of the mixture obtained consistently overlapped with the proton signals of Cd·(1·N2O) and 12·(N2O)2 prepared separately (see Supporting Information, p. 18). In the course of the studies, the complex Pb·(1·N2O3) was also investigated (see Supporting Information, pp. 35–36) and showed 1H–207Pb spin– spin couplings. It was, however, less suited for the present purposes, since the coupling constants were significantly smaller.
Reaction of dialdehyde 2 with the diamine N2O3—formation +2]-macrocycle 22·(N2O3)2 of the [2+ The dialdehyde 2 and the diamine N2O3 (1 equiv each) were dissolved in CD3CN/CDCl3 1:1 at 10 mm concentration in an NMR tube and left to equilibrate at 60 8C. The reaction mixture was then analysed by 1D- and 2D-NMR spectroscopy as well as by MS (MALDI and ESI; see Supporting Information, pp. 13–14) revealing the formation of a [2+ +2]-macrocycle. Although the reaction of dialdehyde 2 with other diamines was investigated (see also references [14b,d]), we focus here on this particular case, which gave the best results for the present purposes. The formation and solid-state molecular structure of the related compound 22·(N2O)2 have already been reported previously (see also Supporting Information, pp. 9–10).[20]
Reaction of dialdehyde 2 with the diamine N2O3 in presence of cadmium ions—metal-templated formation of the macrocyclic complex Cd·(2·N2O3). A mixture of dialdehyde 2, diamine N2O3 and cadmium triflate (1 equiv each) dissolved in CD3CN/CDCl3 1:1 at 10 mm concentration led to the formation of the bis-imine [1+ +1]-macrocycle Cd·(2·N2O3).[22] This macrocyclic complex was characterised by 1D- and 2D-NMR spectroscopy as well as by MS (MALDI and ESI; see Supporting Information, pp. 19–21) and by determination of its solid-state molecular structure (see Supporting Information, p. 21). The solid-state structure shows that the Cd2 + cation is bound to one counterion and two water molecules and not to the oxygen atoms of the diamine component, which is too distant for a direct coordination. Imine-proton– Chem. Eur. J. 2015, 21, 10070 – 10081
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Cd2 + -cation spin–spin splittings are observed in the 1H NMR spectrum (Figure 4; top). The reaction of the dialdehyde 2 and the diamine N2O3 (1 equiv each) was also conducted using only 0.5 equivalents of Cd(OTf)2 in CD3CN/CDCl3 1:1 at 10 mm concentration. The mixture was heated at 60 8C and showed sets of sharp 1H NMR signals corresponding to the Cd·[22·(N2O3)2]
Figure 4. 1H NMR spectra of the complexes Cd·(2·N2O3) and Cd·[22·(N2O3)2] (see Supporting Information, pp. 19-24 for more details). The broad background, observed only after removal of half of the metal ion (bottom spectrum), disappears after completing the titration and removing all the cation (see also text).
(Figure 4; bottom, see also 2D-NMR data in the Supporting Information, pp. 22–24). A broad background is also observed, which is only present after removal of half of the cation, but it disappears at the termination of the titration, on removal of all the cation after addition of hexacyclen. Thus, the broad band could be due to the presence of transient species, notably oligomers, formed from the half amount of reactive free macrocycle generated in the intermediate state and/or that the recondensation of the oligomers to the [2+ +2]-macrocycle is very slow. +2]-complex As efforts to obtain a single crystal of this [2+ failed, a modelling of its equilibrium geometry was pursued using DFT-calculations (B3LYP/6-31G*). The structure calculated presents the expected pattern of a hexacoordinated cation with the imine nitrogen atoms connected by the ligand chains, resulting in a twisted macrocyclic chain centered on Cd (see Supporting Information, p. 24). The same pattern of resolved aliphatic peaks in the 1H NMR spectrum was observed for the dinuclear Cd complex of the [2+ +2]-macrocycle formed by the shorter diamine N2O2 and a similar structure was modelled by DFT (see Supporting Information, pp. 25–27). In order to gain further information about the structures of Cd·[22·(N2O3)2] and Cd·(2·N2O3), 1D-113Cd and 2D-1H–113CdHMQC NMR experiments were performed.[23] Such studies can not only show cross-correlations between the strongly coupled imine protons and the Cd center, but also give indications about the positioning of the oxo–ethylene bridges and corrob-
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Full Paper Generation and behaviour of the strained macrocycles 1·N2O and 2·N2O3 The data presented above set the stage for a study of the features and the fate of the strained [1+ +1]-macrocycles that may be generated upon removal of the stabilizing metal cation by a competing ligand. The high-energy states result from the presence in the free macrocyclic ligands thus obtained of subunit conformations and orientations that do not correspond to their minimum energy form, when not constrained by a macrocyclic structure. One may expect that such out-of-equilibrium entities 1 113 113 Figure 5. H– Cd-HMQC (top) and Cd NMR (bottom) data for the structural investigation of the complexes would present an increased Cd·(2·N2O3) and Cd·[22·(N2O3)2]. strain-induced reactivity induced by their strong tendency to find a way to relax to their lowest energy equilibrium state/strucorate the computed structural proposal for Cd·[22·(N2O3)2] (see ture. Figure 5 and Supporting Information, p. 24). The differences of To investigate such features, we formed the related comchemical shift in the 113Cd NMR spectrum of Cd·(2·N2O3) plexes Cd·(1·N2O), Cd·(2·N2O3) and Cd·[22·(N2O3)2], and studied (¢658.04 ppm) and Cd·[22·(N2O3)2] (¢489.54 ppm), both refertheir behaviour after removal of the metal cation by treatment enced to Cd(OTf)2, are a point of structural argumentation as of the reaction mixtures with hexacyclen. As previously stated, well (Figure 5). As has been reported and discussed,[24] oxygenthe use of Cd2 + as the complexed metal ion brings the advantcontaining ligands, such as certain cryptates, cause an upfield 113 shift for Cd, due to shielding effects. The multiple oxygenage of the appearance of splittings due to 1H–113Cd spin–spin coupling in the 1H NMR spectrum (see Figure 3), which are containing [2.2.2]-cryptand was shown to exhibit a shift of [24b] ¢62 ppm, a valuable indication to determine whether the Cd ion has whereas complexes with nitrogen-containing libeen removed from the complex. It is important to stress that gands, such as bipyridine, were located in a range around the water content of the medium (NMR solvent) plays a crucial + 240 ppm,[25] (in both cases referenced against Cd(ClO4)2). role in the transformations to be examined, since water is Considering the proposed structure of Cd·[22·(N2O3)2], the coneeded for their occurrence through ring opening by hydrolyordination to six nitrogen sites as the main coordinating elesis and ring-size redistribution. ments goes in line with these studies. Furthermore such a difference in NMR shift might be due to the difference in coordination geometry. Whereas Cd·[22·(N2O3)2] can potentially adopt Macrocyclic compounds of dialdehyde 1 a closely octahedral geometry, the complex Cd·(2·N2O3) on the In a first series of experiments, addition of hexacyclen (ca. other hand has a much more distorted structure using differ1.5 equiv) to a solution of separately prepared Cd·(1·N2O) in ent coordination sites, which could also account for the pronounced difference in chemical shift. A similarly distorted CD3CN/CDCl3 1:1 at 10 mm concentration led to the rapid disstructure may be found in a recently reported, but dinuclear, appearance of the H–Cd splittings, indicating that the coordicopper(I) complex.[26] nated metal ion had been quickly removed from the macrocyclic complex. The resulting strained macrocycle 1·N2O generatThe reaction of the shorter diamines N2O and N2O2 with diaed could be observed briefly and then its progressive transforldehyde 2 was also studied (see Supporting Information, mation followed, ending up in the final product identified as pp. 9–10 and pp. 25–27). In both cases the [2+ +2]-macrocycle the [2+ was formed in the free, non-complexed state as well as in the +2]-macrocycle 12·(N2O)2 (Scheme 2 and Figure 6). complexed form with CdII and AgI cations. The solid-state moIt must be stressed that the rate of decay of the initial complex changed from experiment to experiment (from about 6 h lecular structure could be determined for the dinuclear AgI as in Figure 6 to usually less than 15 min), as it was difficult to complex Ag2·[22·(N2O2)2], bearing a molecule of 4-dimethylamicontrol the very small amount of residual water present in the nopyridine coordinated to each Ag center (see the Supporting solution. However, the start and end points of the different Information for details, p. 32). Data for the [2+ +2]-macrocycle runs were well reproducible. Remarkably, transient aldehyde formed with the diamine N2O are also given in the Supporting species were seen to form and then to disappear again at Information. Chem. Eur. J. 2015, 21, 10070 – 10081
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Scheme 2. Representation of the conversion of the [1+ +1]-complex Cd·(1·N2O) into the final strain-released state, the [2+ +2]-macrocycle 12·(N2O)2 (top),via +1]-macrocycle 1·N2O followed by ring opening to transient non-cyclic amino–aldehyde species (bottom), cation removal to give the transient strained [1+ which then undergo recondensation.
open-chain intermediates containing imine and aldehyde +2]groups which thereafter re-condense to give the final [2+ macrocycle 12·(N2O)2. In fact, two sets of aldehyde proton signals were observed, one being much more intense than the other one, indicating that there were at least two different intermediates and that these were undergoing reaction at different rates. It can also be seen that the imine proton signals broaden and shift as the aldehyde signals appear, and then sharpen again with the disappearance of the aldehydes and the formation of the final dimeric macrocycle, indicating that some kind of exchange/rate process was taking place in the intermediate phase. The macrocycles and complexes of dialdehyde 1 formed with the longer diamines N2O2 and N2O3 were prepared, but their behaviour in decay studies was not pursued in detail as it appeared less informative for the present purposes (for details, see Supporting Information pp. 7–8 and pp. 37-42). Macrocyclic compounds of dialdehyde 2
Figure 6. Evolution of the 1H NMR spectrum of the [1+ +1]-complex Cd·(1·N2O) after removal of the Cd cation by addition of 1.5 equivalents of hexacyclen as a function of time from top to bottom. The ¢CH=O proton signals correspond to the formation of transient open-chain amino–aldehyde intermediates (see Figure 7). The shift of the imine ¢CH=N signals is discussed below.
completion of the transformation. The changes observed may thus be attributed to progressive hydrolysis of the imine bonds by the residual water present in the solution, leading to Chem. Eur. J. 2015, 21, 10070 – 10081
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To further investigate the strain-induced reactivity, the behaviour of the complex Cd·(2·N2O3) was also examined. It was expected to connect the strained [1+ +1]-adduct with the relaxed state, the [2+ +2]-adduct (and/or eventually oligomers). Addition of 1.5 equivalents of hexacyclen led to the complete removal of the Cd2 + cation from the macrocyclic complex Cd·(2·N2O3) and to the formation of a new species as observed in the 1 H NMR spectra (Figure 7; top). This species did not present any 1H–113Cd splittings, indicating that it was not complexed to a Cd2 + cation and is thus expected to be the strained free [1+ +1]-macrocycle 2·N2O3. It decayed with a half-life of about
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Figure 7. Top: Evolution of the 1H NMR spectrum of the [1+ +1]-complex Cd·(2·N2O3) after removal of the Cd cation by addition of 1.5 equivalents of hexacyclen as a function of time from top to bottom: at t = 0, after 2, 12 and 22 min, 3.5 h and overnight respectively (from top to bottom). Bottom: +1]-complex Cd·(2·N2O3) after 2 h 10 min of treatment with a) the [1+ 0.5 equiv of hexacyclen b) leading to transient species Cd·[22·(N2O3)2] after 3 h 20 min, c) which then converts into 22·(N2O3)2 d) 10 min after addition of a further 1.0 equivalents of hexacyclen. e) and f) Separately prepared reference samples of 22·(N2O3)2 and Cd·[22·(N2O3)2], respectively (concentrations are 10 mm in all cases). The strong aliphatic signals in the 2.5–3.0 ppm region are due to hexacyclen. For the broad background in spectrum f), see comments for Figure 4 in text. One may note that when the cadmium cations are removed from the macrocycle Cd·(1·N2O), only a weak shift of the NMR signal of the CH=N proton is observed (see Figure 6). The larger shift of 0.3 ppm (see top of this figure) observed in the present case of the macrocycle Cd·(2·N2O3) could be due to the greater flexibility of the diamine chain and the resulting possibility of some fast conformational change.
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12 3 min into the [2+ +2]-macrocycle 22·(N2O3)2, after appearance and disappearance of intermediates visible in the 1H NMR spectra. These intermediates consisted presumably in openchain compounds with aldehyde groups (visible by very weak signals between 10.0 and 10.2 ppm), which then underwent recondensation to give the relaxed [2+ +2]-macrocycle 22·(N2O3)2, in a way similar to the behaviour observed for the Cd·(1·N2O) complex (see Scheme 2). Integration of the water proton signals indicated that these processes took place in the presence of 4 equivalents of water with respect to the starting complex. It should be noted, that the [2+ +2]-macrocycle 22·(N2O3)2 is formed as a main species (estimated to amount to about 70 % from 1H NMR), alongside secondary products, possibly oligomeric materials. Thus, the behaviour of this system (2 + N2O3) is not as clear-cut as the previous one, but is nevertheless informative for the present purposes. In another set of experiments, taking into account the results on the formation of the [2+ +2]-complexes (see above), 0.5 equivalents of hexacyclen were added to a sample of Cd·(2·N2O3) (Figure 7; bottom). Roughly 3 h after the addition and heating to 60 8C to ensure completion of the reaction, the +2]-complex Cd·[22·(N2O3)2] had formed, alongside other sec[2+ ondary products. When the reaction was conducted at room temperature this complex was not obtained within the same time period, as one might expect considering a slower rate for the ring opening and recombination involved in the process. The transformation of one species into the other one could also be followed by examination of the 1H–113Cd splittings, which decreased from 21.0 Hz for Cd·(2·N2O3) to 17.6 Hz for Cd·[22·(N2O3)2]. After the further addition of 1.0 equivalents of hexacyclen, the rapid appearance, within 2 min, of a species identical to a separately prepared sample of 22·(N2O3)2 was observed (again in an purity of about 70 %). The first transformation may be considered to involve the sequence (Scheme 3): 1) initial generation of 0.5 equivalents of strain-free 2·N2O3 macrocycle from Cd·(2·N2O3) by cation removal with 0.5 equiv+2]-macrocycle; alents hexacyclen; 2) 2·N2O3 then gives the [2+ 3) this marcocycle then acts as decomplexing agent towards half of the remaining 0.5 equivalents of Cd·(2·N2O3); 4) the thus progressively liberated free 2·N2O3 in turn gives [2+ +2]macrocycle; 5) the macrocycle then reacts with the remaining Cd·(2·N2O3) complex, resulting in the full transformation of Cd·(2·N2O3) into Cd·[22·(N2O3)2]. This behaviour is in line with the appearance of an operative strain-activated state, that is, the formation of the 2·N2O3 macrocycle. The second transformation is a simple decomplexation of Cd·[22·(N2O3)2] on addition of more hexacyclen to give the uncomplexed [2+ +2]-macrocycle 22·(N2O3)2. With the diamine N2O2 no [1+ +1]-macrocycle is formed, neither with nor without metal, but the [2+ +2]-macrocycle is directly obtained. N2O2 appears to be too short to form a [1+ +1]macrocyclic complex. The same also holds for the N2O diamine. Only the cadmium complex of the [2+ +2]-macrocycle 22·(N2O2)2 could be identified.
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Scheme 3. Structural representation of the transition of the [1+ +1]-complex Cd·(2·N2O3) through the respective intermediates Cd·[22·(N2O3)2] and 2·N2O3 to reach the final common strain released state 22·(N2O3)2.
Theoretical evaluation of the energetics of the structures 1·N2O and 2·N2O3 and of their strain-induced transformations To gain insight into the energetics of the transformations described above, and in particular into the occurrence of strain-induced reactivity, Hartree–Fock calculations were performed on the molecular structures of the free macrocyclic ligands 1·N2O and 2·N2O3. The high reactivity of these species is reflected in their short lifetime in the conditions of the experiments and the formation of thermodynamically stable relaxed derivatives. Hartree–Fock (HF; 6-311 + G**) calculations have been performed on model structures presenting the main structural features of these macrocycles.[27] These incorporate in particular subunits reminiscent of the cisoid (c) f-NCCN- = 08 and transoid (t) f-NCCN- = 1808 conformations of 2,2’-bipyridine, for which computational results have indicated that the former is about 30 kJ mol¢1 less stable than the latter, representing respective global maxima and minima.[12d] The reason for these energetic differences can be found in manifold factors, such as lone pair repulsions between nitrogen atoms (destabilizing the c-form), steric repulsions between protons (destabilizing the c-form), pconjugation effects of the aromatic systems (destabilizing outof-plane rotations), and attractive interactions between aromatic protons and N-lone pairs (stabilizing the t-form). One may consider that similar effects influence the reactivity of the systems discussed in this work. To simplify these and reduce computational cost, the chains of the diimine linkers in the macrocycles 1·N2O and 2·N2O3 were replaced by methyl groups to give the model compounds 1·(NMe)2 and 2·(NMe)2. HF calculations were performed on two rotationally restricted rotamers of 2·(NMe)2 corresponding to N-C-C-N dihedral angles of 08 and 1808 (Scheme 4). Therefore, the structures of 1·(NMe)2 and 2·(NMe)2 were maintained in planar form. For 2·(NMe)2, the energy difference was found to be about 5.1 kcal mol¢1 between the tt and ct forms and 6.9 kcal mol¢1 between the ct and the cc forms, adding up to a total energy difference Chem. Eur. J. 2015, 21, 10070 – 10081
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Scheme 4. Rotamer energies for 2·(NMe)2.The arrows indicate cisoid conformations about N-C-C-N bonds, stressing the lone pair-repulsions.
of 12.0 kcal mol¢1, to be compared to 12.1 kcal mol¢1 directly between the cc and tt forms. These results show that the computed energy differences between the structures add up satisfactorily. They also indicate that the removal of the metal cation from the Cd·(2·N2O3) complex, in which the ligand conformation is stabilised by the binding of the cation, liberates a species of very significant strain energy that strongly enforces the molecule to relax and thus may be expected to cause a marked ring strain-induced reactivity enhancement, driving the rapid cleavage of the ring and the recombination of the fragments generated into the relaxed dimeric [2+ +2]-macrocycle 22·(N2O3)2. Thus, the diamine N2O3 condenses with the 2,6pyridinedicarboxaldehyde 2 in the W form to give the strainfree [2+ +2]-macrocycle. The model compound 1·(NMe)2 gave results for the relative energies of the different conformations that were comparable to those computed for 2·(NMe)2 (Scheme 5). Considering that the conformations of the core tri-nitrogen unit of 1·(NMe)2 have features similar to those computed for 2·(NMe)2, computations were performed only on the U shape cisoid–cisoid form and on the two additional cisoid–transoid orientations of the imine groups for 1·(NMe)2. Since the dialdehyde 1 is non-symmetric, there are of course two different “mixed” states with f-
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Full Paper In the present case, the transient free macrocycles 1·N2O and 2·N2O3 rapidly decay and form the corresponding [2+ +2]-macrocycles 12·(N2O)2 and 22·(N2O3)2 via open-chain (aldehyde–amine) intermediates (see above and Figures 6 and 7, and Schemes 2 and 3). It is also probable, that the origin of reactivity of the [1+ +1]macrocycles also lies in their accumulated strain energy. Indeed, the reactivity of the imine bonds would be enhanced in the free macrocycles 1·N2O and 2·N2O3 by straining of the imine C(sp2)= N(sp2) unit, increasing its propensity to relax to a C(sp3)¢N(sp3) state by the addition of a nucleophile, namely water. Consequently, the hydrolysis of the imine functional group is facilitated, generating an open-chain intermediate, which subsequently can recondense to give the signifiScheme 5. Rotamer energies 1·(NMe)2. The arrows indicate cisoid conformations about N-C-C-N bonds, stressing the lone pair-repulsions. +2]-macrocantly less strained [2+ cycles or other cyclic and noncyclic oligomeric entities. The increased reactivity of the [1+ +1]-macrocycles is also highlighted NCCN- = 0–1808 and f-NCCN- = 180–08 respectively. The first transby the fact that the final compound obtained is the [2+ oid to cisoid change resulted in the energy differences DE180– +2]-mac¢1 rocycle, meaning that the former opens up by dissociation of and DE180–1808!0–1808 = 6.8 kcal mol¢1, 1808!180–08 = 5.1 kcal mol the strained imine bonds and then recondenses to the compawhereas the second cisoid form gave DE180–08!0–08 = 10.5 kcal ratively unstrained imine groups of the latter, rather than remol¢1 and DE0–1808!0–08 = 8.8 kcal mol¢1. More details about the maining open chain. relative energies of the different conformations are representIndications in favour of an increased reactivity of the C=N ed in Scheme 5. Overall, the results obtained for both cases unit by strain-induced distortion of the C=N¢R angle from the studied here are in line with the reported computations on the formal unstrained 1208 towards a larger angle may be gained conformations of bipyridine itself.[12] from theoretical studies of in-plane nitrogen inversion of Since the present calculations concern model compounds, imines.[28] Indeed, ab initio computations on the in-plane nitrothey omit additional effects that may be present in the ringgen inversion of imines, show that the change in electronic closed structure of the macrocycles incorporating the nitrogen charge distribution from the bent ground state to the linear containing cores of the models 1·(NMe)2 and 2·(NMe)2, mean+),N(¢) polarity, ing that the actual energy differences of the different forms of transition state leads to an increase in the C(+ thus facilitating reaction of a nucleophile at the carbon center the closed macrocycles could even be significantly higher than of the imine group. In line with these considerations, the signal those obtained here. of the imine proton is at 8.45 ppm for the demetallated [1+ +1]macrocycle 2·N2O3 and at 8.30 ppm for the [2+ +2]-macrocycle 22·(N2O3)2 (Figure 7). This upfield shift of about 0.15 ppm beOrigin of the enhanced reactivity of the macrocycles 1·N2O tween the strained [1+ +1]-macrocycle and the resting [2+ +2]and 2·N2O3 macrocycle fits with an increase in positive charge on the carbon site and thus with a distortion of the C=N¢C angle toWe showed previously[10] that steric strain caused by CH3/CH3 wards linearity. interaction on introduction of methyl groups at the C and N One may also note that in the strained [1+ sites at the ends of the C=N¯¢N¯ unit of the hydrazone C +1]-macrocycles (Figure 1) caused a marked twist around the N¢N bond, thus distortion/rotation of the C¢CH=N¢ group out of the pyridine decreasing conjugation within the C=N¯¢N¯ fragment and leadplane should both deconjugate it from the pyridine group and ing to a significant increase of the reactivity of the hydrazone change its orientation with respect to the pyridyl nitrogen, bond. As a consequence, constitutional dynamic exchange repossibly causing some destabilisation. Somewhat related is the actions were markedly facilitated. fact that pyridine-2-aldehyde forms a larger amount of imine Chem. Eur. J. 2015, 21, 10070 – 10081
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Full Paper (61 %) with isopentylamine than benzaldehyde (20 %).[29] Both of the strain-induced structural effects evoked, that is, in-plane distorsion and out-of plane rotation, lead in the direction of a less stable/more reactive imine group. Thus, the origin of the strain-enhanced reactivity observed herein for the [1+ +1]-macrocycles 12·(N2O)2 and 22·(N2O3)2 can be manifold, with contributions from various effects resulting from strain-induced structural distorsion. From another point of view of much significance with respect to the perspectives of coupling constitutional dynamic chemistry to out-of-equilibrium and dissipative processes, one notes that the strained [1+ +1]-macrocycles 1·N2O and 2·N2O3 represent kinetically trapped out-of-equilibrium, high-energy states that progressively relax to the corresponding thermody+2]-macronamically stable states composed of the derived [2+ cycles and eventually oligomeric entities. Thus, the strain-enhanced reactivity observed is driven by an out-of-equilibrium to equilibrium conversion process. For clarity, the full set of transformations is summarised in Scheme 6 for the specific case involving the 1, N2O and Cd2 + components.
Cd·(2·N2O3) here) the macrocyclic ligand is maintained in a markedly strained conformation by the coordination forces of the metal cation. 2) The removal of the coordinated metal cation from these complexes generates highly strain-free macrocycles (e.g., 1·N2O and 2·N2O3), which incorporate various structural deformations with respect to their preferred, relaxed state. These are very reactive and release their strain by undergoing ring opening through rapid hydrolysis by trace amounts of water in the reaction medium. 3) These reactive metal-free macrocycle intermediates (e.g., 1·N2O and 2·N2O3) can be considered as constituting an out-of-equilibrium state, which progressively attains equilibrium by converting into a thermodynamically stable state, comprising the relaxed [2+ +2]-macrocycles (e.g., 12·(N2O)2 and 22·(N2O3)2) and eventually oligomeric entities. Such out-of-equilibrium states may be generated in various ways such as substrate binding (e.g., metal cation coordination here), photoactivation, phase separation[30,31] and so forth, and harnessed to drive chemical transformations.
Experimental Section Typical experiment: The dialdehyde and the corresponding metal triflate (considering a final concentration of 10 mm) were taken up in 500 mL of CDCl3/CD3CN 1:1, mixed and transferred into an NMR tube. Subsequently a solution of the corresponding diamine in 200 mL (10 mm in CDCl3/CD3CN 1:1, vide supra) was added to the NMR tube, the sample thoroughly mixed and the formation of the corresponding compounds was followed by NMR spectroscopy after equilibrating at room temperature or 60 8C. For the removal of the cation from the complexes, the corresponding amount of the hexacyclen (e.g., 0.5 or 1.5 equiv) was dissolved in 100 mL of the same solvent, added to the NMR-tube and the course of the reaction followed directly.
Scheme 6. Representation of the set of transformations undergone by the dynamic covalent system comprising the components 1, N2O and Cd2 + . It proceeds via the generation of a high energy out-of-equilibrium state, the transient free macrocycle 1·N2O (bottom center) presenting strain-induced reactivity and involves constitutional switching between a “metallo-macrocycle state” stabilised by metal cation coordination (right) and an uncomplexed “resting state” (left) in response to shape change of component 1 on cation biding and removal.
General descriptions and characterisations: See Supporting Information. CCDC 1055945 and 1055946 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
Conclusion The results reported above highlight the operation of structural features of various types that impose a high energy state on a chemical entity and thus enforce an increase in reactivity. They lead to several conclusions that may be summarised as follows. 1) In the well-known bis-imine macrocyclic complexes obtained by templated synthesis (e.g., Cd·(1·N2O) and Chem. Eur. J. 2015, 21, 10070 – 10081
Details for NMR spectroscopy: For NMR spectra recorded in CDCl3/CD3CN, the CH3CN peak was chosen for calibration. The NMR solvents were filtered as received (Sigma–Aldrich or EurisoTop) through a pad of Al2O3 and subsequently stored over freshly activated molecular sieves (3 æ) under exclusion of light.
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We thank the NMR spectroscopy and mass spectrometry services of the Universit¦ de Strasbourg. We thank the ANR (2010 BLAN-717-1 grant) and the ERC (Advanced Research Grant SUPRADAPT 290585) for financial support. G.V. thanks the MinistÀre de l’Enseignement Sup¦rieur et de la Recherche for a doctoral fellowship. L.R. thanks the Wissenschaftsportal—Franzçsische Botschaft in Deutschland for a post-doctoral fellowship. We thank Dr. Jean-Louis Schmitt for his valuable help with
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Full Paper NMR measurements and valuable discussions and assistance. We would like to express our gratitude to Dr. Gustavo Pierdominici-Sottile and Dr. Ezequiel Juritz from the National University of Quilmes (Argentina) for their valuable help with the computational studies. Keywords: dynamic covalent chemistry (DCC) · imines · macrocycles · out-of-equilibrium · strained molecules [1] a) A. von Baeyer, Ber. Dtsch. Chem. Ges. 1885, 18, 2269 – 2281; b) K. B. Wiberg, Angew. Chem. Int. Ed. Engl. 1986, 25, 312 – 322; Angew. Chem. 1986, 98, 312 – 322. [2] The term entasis was first used in the context of metalloenzymes, see for instance: B. L. Vallee, R. J. P. Williams, Proc. Natl. Acad. Sci. USA 1968, 59, 498 – 505. [3] a) H. Sachse, Ber. Dtsch. Chem. Ges. 1890, 23, 1363 – 1370; b) H. Sachse, Z. Phys. Chem. 1892, 10, 201 – 241; c) H. Sachse, Z. Phys. Chem. 1893, 11, 185 – 219. [4] See for instance deformations due to diaxial methyl–methyl interactions on cyclohexane rings in triterpenes: a) J.-M. Lehn, J. Levisalles, G. Ourisson, Tetrahedron Lett. 1961, 2, 682 – 686; b) J.-M. Lehn, J. Levisalles, G. Ourisson, Bull. Soc. Chim. Fr. 1963, 1096 – 1101. [5] E. L. Eliel, S. H. Willen, Stereochemistry of Organic Compounds, Wiley, New York, 1994. [6] a) K. Tani, B. M. Stoltz, Nature 2006, 441, 731 – 734; b) J. Clayden, Nature 2012, 481, 274 – 275; c) J. Clayden, W. J. Moran, Angew. Chem. Int. Ed. 2006, 45, 7118 – 7120; Angew. Chem. 2006, 118, 7276 – 7278. [7] A. J. Kirby, I. V. Komarov, P. D. Wothers, N. Feeder, Angew. Chem. Int. Ed. 1998, 37, 785 – 786; Angew. Chem. 1998, 110, 830 – 831. [8] a) V. Somayaji, R. S. Brown, J. Org. Chem. 1986, 51, 2676 – 2686; b) H. Slebocka-Tilk, R. S. Brown, J. Org. Chem. 1987, 52, 805 – 808; c) A. J. Bennet, Q. P. Wang, H. Slebocka-Tilk, V. Somayaji, R. S. Brown, B. D. Santarsiero, J. Am. Chem. Soc. 1990, 112, 6383 – 6385; d) J. I. Mujika, J. M. Mercero, X. Lopez, J. Am. Chem. Soc. 2005, 127, 4445 – 4453; e) B. Wang, Z. Cao, Chem. Eur. J. 2011, 17, 11919 – 11929. [9] J. Y. W. Mak, R. H. Pouwer, C. M. Williams, Angew. Chem. Int. Ed. 2014, 53, 13664 – 13688; Angew. Chem. 2014, 126, 13882 – 13906. [10] G. Vantomme, S. Jiang, J.-M. Lehn, J. Am. Chem. Soc. 2014, 136, 9509 – 9518. [11] The corresponding arrangement is reminiscent of a diaxial methyl – methyl interaction on a cyclohexane ring, which amounts to about 4.0 Kcal mol¢1; see: N. L. Allinger, M. A Miller, J. Am. Chem. Soc. 1961, 83, 2145 – 2146. [12] Calculations yield a preference of 2,2’-bipyridine for the transoid with respect to cisoid form by about 25–30 kJ mol¢1: a) S. T. Howard, J. Am. Chem. Soc. 1996, 118, 10269 – 10274; b) A. Gçller, U.-W. Grummt, Chem. Phys. Lett. 2000, 321, 399 – 405; c) G. Corongiu, P. Nava, Int. J. Quantum Chem. 2003, 93, 395 – 405. For structural and spectroscopic data, see: d) L. L. Merritt Jr., E. D. Schroeder, Acta Crystallogr. 1956, 9, 801 – 804; e) F. Bertinotti, A. M. Liquori, R. Pirisi, Gazz. Chim. Ital. 1956, 86, 893 – 898; f) K. Nakamoto, J. Phys. Chem. 1960, 64, 1420 – 1425; g) S. Castellano, H. Gunther, S. Ebersole, J. Phys. Chem. 1965, 69, 4166 – 4176; h) I. C. Calder, T. M. Spotswood, C. I. Tanzer, Aust. J. Chem. 1967, 20, 1195 – 1212; i) V. Barone, C. Minichino, S. Fliszar, N. Russo, Can. J. Chem. 1988, 66, 1313 – 1317; j) C. Jaime, J. Font, J. Org. Chem. 1990, 55, 2637 – 2644. [13] a) G. S. Hanan, J.-M. Lehn, N. Kyristakas, J. Fischer, J. Chem. Soc. Chem. Commun. 1995, 765 – 766; b) M. Ohkita, J.-M. Lehn, G. Baum, D. Fenske, Chem. Eur. J. 1999, 5, 3471 – 3481. [14] a) M. Barboiu, J.-M. Lehn, Proc. Natl. Acad. Sci. USA 2002, 99, 5201 – 5206; b) M. Barboiu, G. Vaughan, N. Kyritsakas, J.-M. Lehn, Chem. Eur. J. 2003, 9, 763 – 769; c) A.-M. Stadler, J. Ramirez, J.-M. Lehn, Chem. Eur. J. 2010, 16, 5369 – 5378; d) A.-M. Stadler, J.-M. Lehn, J. Am. Chem. Soc. 2014, 136, 3400 – 3409. [15] a) B. Dietrich, P. Viout, J.-M. Lehn, Macrocyclic Chemistry: Aspects of Organic and Inorganic Supramolecular Chemistry, Wiley-VCH, Weinheim, 1993; b) L. A. Wessjohann, D. G. Rivera, F. Leûn, Org. Lett. 2007, 9, 4733 – 4736; c) D. B. Amabilino, J. F. Stoddart, Chem. Rev. 1995, 95, 2725 – 2828; d) P. T. Glink, A. I. Oliva, J. F. Stoddart, A. J. P. White, D. J. WilChem. Eur. J. 2015, 21, 10070 – 10081
www.chemeurj.org
[16] [17]
[18]
[19]
[20] [21] [22]
[23] [24]
[25] [26] [27]
[28]
10080
liams, Angew. Chem. Int. Ed. 2001, 40, 1870 – 1875; Angew. Chem. 2001, 113, 1922 – 1927; e) B. H. Northrop, F. Aricû, N. Tangchiavang, J. D. Badjic´, J. F. Stoddart, Org. Lett. 2006, 8, 3899 – 3902; f) A. R. Williams, B. H. Northrop, T. Chang, J. F. Stoddart, A. J. P. White, D. J. Williams, Angew. Chem. Int. Ed. 2006, 45, 6665 – 6669; Angew. Chem. 2006, 118, 6817 – 6821; g) I. T. Harrison, S. Harrison, J. Am. Chem. Soc. 1967, 89, 5723 – 5724. N. F. Curtis, Coord. Chem. Rev. 1968, 3, 3 – 47. a) J.-M. Lehn, Chem. Eur. J. 1999, 5, 2455 – 2463; b) S. J. Rowan, S. J. Cantrill, G. R. Cousins, J. K. M. Sanders, J. F. Stoddart, Angew. Chem. Int. Ed. 2002, 41, 898 – 952; Angew. Chem. 2002, 114, 938 – 993; c) P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor, J. K. M. Sanders, S. Otto, Chem. Rev. 2006, 106, 3652 – 3711; d) J.-M. Lehn, Chem. Soc. Rev. 2007, 36, 151 – 160; e) S. Ladame, Org. Biomol. Chem. 2008, 6, 219 – 226; f) B. L. Miller Dynamic Combinatorial Chemistry, Wiley, Chichester, 2010; g) J. N. H. Reek, S. Otto, Dynamic Combinatorial Chemistry, Wiley-VCH, Weinheim, 2010; h) R. A. R. Hunt, S. Otto, Chem. Commun. 2011, 47, 847 – 855; i) M. E. Belowich, J. F. Stoddart, Chem. Soc. Rev. 2012, 41, 2003 – 2024; j) J.-M. Lehn, M. Barboiu, Topics Curr. Chem 2012, 322, 1 – 32; k) J.-M. Lehn, Angew. Chem. Int. Ed. 2013, 52, 2836 – 2850; Angew. Chem. 2013, 125, 2906 – 2921. a) S. Ulrich, E. Buhler, J.-M. Lehn, New J. Chem. 2009, 33, 271 – 292; b) S. Ulrich, J.-M. Lehn, Angew. Chem. Int. Ed. 2008, 47, 2240 – 2243; Angew. Chem. 2008, 120, 2272 – 2275; c) S. Ulrich, J.-M. Lehn, J. Am. Chem. Soc. 2009, 131, 5546 – 5559. The case of N2O2 was studied as well and gave similar and conclusive results but the SIR behaviour was more difficult to analyse (see Supporting Information, pp. 7,11,25 and 37). P. C. Haussmann, S. I. Khan, J. F. Stoddart, J. Org. Chem. 2007, 72, 6708 – 6713. P. D. Ellis, Science 1983, 221, 1141 – 1146. a) D. E. Fenton, R. Leonaldi, Inorg. Chim. Acta 1981, 55, L51 – L53; b) A. Freira, R. Bastida, L. Valencia, A. Macas, C. Lodeiro, H. Adams, Inorg. Chim. Acta 2006, 359, 2383 – 2394; c) H. Adams, N. A. Bailey, D. E. Fenton, Y.-S. Ho, Inorg. Chim. Acta 1993, 212, 65 – 68; d) R. Menif, D. Chen, A. E. Martell, Inorg. Chem. 1989, 28, 4633 – 4639. D. Live, I. M. Armitage, D. C. Dalgarno, D. Cowburn, J. Am. Chem. Soc. 1985, 107, 1775 – 1777. a) P. S. Marchetti, S. Bank, T. W. Bell, M. A. Kennedy, P. D. Ellis, J. Am. Chem. Soc. 1989, 111, 2063 – 2066; b) P. G. Mennitt, M. P. Shatlock, V. J. Bartuska, G. E. Maciel, J. Phys. Chem. 1981, 85, 2087 – 2091. M. Munataka, S. Kitagawa, F. Yagi, Inorg. Chem. 1986, 25, 964 – 970. M. Hutin, G. Bernardinelli, J. R. Nitschke, Proc. Natl. Acad. Sci. USA 2006, 103, 17655 – 17660. a) The molecular conformations of the macrocycle-fragments were investigated by computational approaches, using the Spartan ’10[27b] software package from Wavefunction Inc. (Scheme 4; standard Windows personal computer) or Gaussian 09[27c] (Scheme 5; computation facility in Quilmes, Argentina) respectively. The calculations were performed using Hartree–Fock methods with 6-311 + G** basis sets. Overall planarity and geometry was conserved, and free energies calculated and compared. Structural optimisations for Cd·[22·(N2O2)2] and Cd·[22·(N2O3)2] were carried out on a DFT-level (gas-phase), using RB3LYP-6-31-G* with an overall charge of + 2; b) Spartan ’10, Wavefunction, Inc., Irvine, CA; c) Gaussian 09, Revision A.02-SMP, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, ©. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc. Wallingford CT, 2009. a) J.-M. Lehn, B. Munsch, P. Millie, Theor. Chim. Acta. 1970, 16, 351 – 372; b) J. Glvez, A. Guirado, J. Comput. Chem. 2010, 31, 520 – 531 and private communication. Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper [29] P. Kovarˇcˇek, J.-M. Lehn, J. Am. Chem. Soc. 2012, 134, 9446 – 9455 and Table 1 therein. [30] N. Hafezi, J.-M. Lehn, J. Am. Chem. Soc. 2012, 134, 12861 – 12868.
[31] J.-M. Lehn, Angew. Chem. Int. Ed. 2015, 54, 3276 – 3289; Angew. Chem. 2015, 127, 3326 – 3340. Received: March 26, 2015 Published online on June 8, 2015
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& Dynamic Chemistry
Strain-Induced Reactivity in the Dynamic Covalent Chemistry of Macrocyclic Imines Lars Ratjen,[a, b, c] Ghislaine Vantomme,[a] and Jean-Marie Lehn*[a] Abstract: The displacement of molecular structures from their thermodynamically most stable state by imposition of various types of electronic and conformational constraints generates highly strained entities that tend to release the accumulated strain energy by undergoing either structural changes or chemical reactions. The latter case amounts to strain-induced reactivity (SIR) that may enforce specific chemical transformations. A particular case concerns dynamic covalent chemistry which may present SIR, whereby reversible reactions are activated by coupling to a high-energy state. We herewith describe such a dynamic covalent chemical (DCC) system involving the reversible imine formation reaction. It is based on the formation of strained macrocyclic bis-imine metal complexes in which the macrocyclic ligand is in a high energy form enforced by the coordination of the metal cation. Subsequent demetallation generates a highly strained free macrocycle that releases its accumulated strain energy by hydrolysis and reassembly into a resting state.
Introduction Chemical reactions are influenced by a variety of physical (pressure, temperature, light, etc.), and physicochemical factors, such as concentration, solubilities of reactants and products, additives, catalysts, as well as structural features of the reactants. Among the last, a factor which can markedly affect reactivity as well is strain in general and ring-strain in particular.[1] Strained molecules have an intrinsic entasis[2] (from the Greek word for tension), a driving force for chemical reactions. Without strain-induced reactivities, epoxide resins would not polymerise and aziridines would not react readily. Cyclic molecules [a] Dr. L. Ratjen, Dr. G. Vantomme, Prof. Dr. J.-M. Lehn Laboratoire de Chimie Supramol¦culaire, ISIS Universit¦ de Strasbourg 8 All¦e Gaspard Monge, 67000 Strasbourg (France) E-mail: [email protected] [b] Dr. L. Ratjen Fundaciûn Fraunhofer Chile Research Mariano Snchez Fontecilla 310, Piso 14, Las Condes, Santiago, (Chile) [c] Dr. L. Ratjen Facultad de Biologa Center for Bioinformatics and Integrative Biology (CBIB) Universidad Andres Bello, Av. Republica 239, Santiago (Chile) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201501192. Chem. Eur. J. 2015, 21, 10070 – 10081
Specifically, the metal-templated condensation of a dialdehyde with a linear diamine leads to a bis-imine [1+ +1]-macrocyclic complex in which the macrocyclic ligand is in a coordination-enforced strained conformation. Removal of the metal cation by a competing ligand yields a highly reactive [1+ +1]-macrocycle, which then undergoes hydrolysis to transient non-cyclic aminoaldehyde species, which then recondense to a strain-free [2+ +2]-macrocyclic resting state. The process can be monitored by 1H NMR spectroscopy. Energy differences between different conformational states have been evaluated by Hartree–Fock (HF) computations. One may note that the stabilisation of high-energy molecular forms by metal ion coordination followed by removal of the latter, offers a general procedure for producing out-of-equilibrium molecular states, the fate of which may then be examined, in particular when coupled to dynamic covalent chemical processes.
usually tend to release ring strain through structural deformations, such as bond-twisting, internally stabilizing their structure. The cyclohexane molecule adopts its non-planar chair and twisted-boat conformations to avoid the angle strain that would be caused by the deformation of the six sp3-hybridised carbon atoms in a planar hexagonal geometry, as already shown by Sachse at the end of the 19th century.[3] Nonbonded interactions between sterically demanding groups or between heteroatoms with lone pairs result in strain accumulation that leads to various types of deformations, notably in cyclic structures[4] and are basic features of conformational analysis.[5] Twisted amides, such as A[6] and B[7] present strainand distortion-induced reactivities markedly different from those of stereotypical amides (Figure 1).[8] The amide (peptide) bond plays a major role in nature as it connects the amino acid residues in proteins. The optimal conjugation of the nitrogen lone pair electrons with the carbonyl function in the planar amide group leads to the usual stability and lack of reactivity of amides towards nucleophiles. In the twisted amides A and B, in which the amide group is located at a bridgehead, such ideal electron delocalisation is Bredt’s rule-forbidden,[9] strongly influencing their reactivity by decreasing their stability and inertness towards nucleophilic attack.[6–8] As an example of reactivity induced by strain due to sterically demanding groups, we have recently reported that the in-
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Figure 1. Typical lone-pair/carbonyl conjugation (top) is prevented in the representative bridgehead twisted amides A[6] and B,[7] which present atypical reactivities. A strain-activated hydrazone C[10] is also shown.
troduction of two methyl groups in the hydrazone C[10] markedly enhances its reactivity towards the dynamic covalent exchange of the hydrazine component as a result of the distortion from planarity of the C=N¢N¢Me group that decreases the conjugation between the nitrogen C¢N¢Me electronic lone pair and the C=N double bond.[11] Besides activation by such steric repulsion and by angular deformation, very significant strain may be generated by the overall electronic effects due to heteroatoms. An emblematic case is that of 2,2’-bipyridine, which is about 30 kJ mol¢1 less stable in its cisoid form than in its transoid one.[12] This strong orientational effect has been implemented for the enforced generation of helically wrapped molecular strands.[13] Conversely, the binding of metal cations to these strands causes their unwrapping into the cisoid orientations of the N,N’-subunits leading to metal complexes in which the coordinated ligands adopt high-energy linear shapes stabilised by the binding energy of the metal ions. On removal of these cations from the complexes, the ligands immediately return to their much more stable helical form, providing also for the possibility to generate reversible extension/contraction molecular motions.[14] We herewith report that such strong structure-enforcing effects may be recruited towards the induction of strain-induced reactivity. Indeed, macrocyclic ligands in a highly strained state can be generated by metal-templated synthesis, whereby metal-ion complexation enforces a high-energy conformation of the ligand, the strain energy accumulated in the ligand being overcompensated by the binding energy of the metal cation(s) to the coordinating (nitrogen) heteroatoms.[15, 16] Hence, the removal of the coordinated metal ion by a superior competitive ligand may be expected to result in the formation of a highly strained free macrocycle in which the heteroatomic subunits are in an unstable orientation constrained by the cyclic structure. This is in particular the case for macrocyclic ligands incorporating coordination subunits, such as 2,2’-bipyridine (or terpyridine), as noted above. From the point of view of constitutional dynamic chemistry (CDC),[17] the generation of such highly strained entities by demetallation opens up very interesting possibilities towards the activation of constitutional modification through component reorganisation and exchange processes. Chem. Eur. J. 2015, 21, 10070 – 10081
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We have previously described a system that displays combined constitutional and morphological dynamics, in which the morphological change triggered by the binding and removal of a metal ion results in a reversible constitutional interconver+1]-macrocycle and an uncomsion between a complexed [1+ plexed free ligand state that may contain the corresponding [2+ +2]-macrocycle (together with linear oligomers) (Scheme 1).[18] This process is based on the ability to switch a tridentate terpyridine-type coordination subunit reversibly between an “extended” W-shaped state and a “compact” Ushaped state through the binding and removal of a metal ion.[18c]
Scheme 1. Schematic representation of the principle of strain-induced reactivity through the generation of an out-of-equilibrium high-energy state in a dynamic covalent system. It implements constitutional switching between a “metallo-macrocycle state” (right) and an uncomplexed “resting state” (left) in response to W-U shape changes and proceeds through a strained free macrocycle (center). The overall process involves the following steps: 1) reversible switching of the ligand molecule from the free W shape to the U +1]-macrocycle forshape in the complex on cation coordination (top); 2) [1+ mation on condensation with a difunctional chain via a covalent dynamic connection (right); 3) removal of the metal cation with generation of a strain+1]-macrocycle presenting strain-induced reactivity (bottom); 4) relaxaed [1+ +2]-macrocycle tion to the thermodynamically stable state comprising the [2+ +1]-macrocycle represents and eventually some oligomers (left); 5) the [1+ a kinetically trapped out-of-equilibrium high energy state. The direction of the arrows indicates the orientation of the aldehyde functional groups in the dialdehyde compounds 1 and 2. “Metallo-macrocycle state” and “resting +1]-macrocycle and the unstate” designate respectively the complexed [1+ complexed relaxed product(s), the [2+ +2]-macrocycle, eventually together with linear oligo(poly)mers depending on the diamine.
The structures of the molecules and metal complexes investigated herein are represented in Figure 2. Thus, the dialdehyde 1 in its preferred W-shaped form undergoes polycondensation with a diamine to give a [2+ +2]-macrocycle (e.g. 12·(N2O)2) and/or linear oligo(poly)mers, depending on the diamine.[18] The binding of a metal ion to 1 results in switching the W-shaped core into a U-shaped one in which the dialdehyde functions are held in an orientation favouring the formation of a macrocycle on reaction with a suitable diamine, as exemplified by structure Cd·(1·N2O) (Figure 2). A similar behaviour is presented by the bis-imines formed by pyridine-2,6-di-
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Figure 2. Structures of the molecules and metal complexes considered herein. Note that the bis-imine subunits in the free macrocyclic ligands 12·(N2O)2 and 22·(N2O3)2 are represented in their energetically preferred conformation.
carboxaldehyde 2 with linear diamines (Figure 2). These systems display reversible switching between macrocyclic complex and uncomplexed “free” (large macrocycle and/or oligo(poly)mer) states upon coordination of a metal ion or its removal by the addition of a competitive binder. The involved reactions (imine formation, imine exchange, complexation and decomplexation) are carried out at equilibrium condition and can be followed by 1H NMR spectroscopy. Considering the above comments, the crucial feature in the observed transformation from the macrocyclic complex to the uncomplexed products resides in the formation of a highly strained macrocyclic free ligand upon removal of the metal cation. It led us to investigate in more detail the strain-induced reactivity (SIR) resulting from the unfavourable interactions ac+1]-macrocyclic ligand structure by cumulated in the free [1+ following its fast transformation into strain-relaxed products by 1 H NMR monitoring of the transient demetallated macrocycle(s). In particularly, the expected strainless products would be [2+ +2]-macrocycle and/or linear oligo(poly)mers depending on the nature of the diamine. In the following, “free state” or “relaxed state” will be used to designate the state of the system characterised by these uncomplexed strainless products.
Results and Discussion In order to investigate the transformation undergone by the free macrocycles generated by removal of the metal cations from the corresponding macrocyclic complexes, it was first necessary to establish in separate experiments, the nature of the compounds formed by reaction of dialdehydes 1 and 2 with the diamines N2O and N2O3 in absence and in presence of metal cations.[19] Chem. Eur. J. 2015, 21, 10070 – 10081
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Reaction of dialdehyde 1 with the diamine N2O—formation +2]-macrocycle 12·(N2O)2 of the (dimeric) [2+ We explored the resting state formed between the dialdehyde 1 and the diamine N2O. Compounds 1 and N2O (1 equiv each) were dissolved in CD3CN/CDCl3 1:1 at 10 mm concentration in an NMR tube and left to equilibrate at 60 8C. This reaction mixture was then analysed by 1D- and 2D-NMR spectroscopy as well as by MS (MALDI and ESI; see Supporting Information, pp. 5–6) revealing the formation of a [2+ +2]-macrocycle 12·(N2O)2, which was fully characterised in earlier work.[18a] Also the NOESY spectral data support the relaxed W form. The solid-state structure for an analogous derivative of the dialdehyde 2 also displays a W shape.[20] Reaction of dialdehyde 1 with the diamine N2O in presence of cadmium ions—metal-templated formation of the macrocyclic complex Cd·(1·N2O). As metal cation we chose to work with cadmium instead of the previously used zinc, mercury and lead cations[18] in view of the nuclear spin of 1/2 of the 111Cd and 113Cd isotopes, resulting in the observation of proton–cadmium spin–spin coupling in the 1H NMR spectra of Cd2 + complexes.[21] A mixture of dialdehyde 1, diamine N2O and cadmium triflate (1 equiv each) dissolved in CD3CN/CDCl3 1:1 at 10 mm concentration led to the formation of the bis-imine [1+ +1]-macrocycle Cd·(1·N2O). This macrocyclic complex was characterised by 1Dand 2D-NMR spectroscopy, Cd-NMR spectroscopy as well as by MS (MALDI and ESI; see Supporting Information, pp. 15–18). The imine peaks showed a coupling pattern in which the coupling constants with the two Cd isotopes 111Cd and 113Cd differed by roughly 1 Hz (Figure 3).
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Figure 3. Illustration of the H–CdJ-coupling pattern with the two of the macrocyclic complex Cd·(1·N2O).
111
Cd and 113Cd isotopes in the 1H NMR spectrum
Interestingly, when only 0.5 equivalents of Cd(OTf)2 was used, a defined mixture of the [1+ +1]-complex Cd·(1·N2O) and the [2+ +2]-macrocycle 12·(N2O)2 was observed. The NMR signals of the mixture obtained consistently overlapped with the proton signals of Cd·(1·N2O) and 12·(N2O)2 prepared separately (see Supporting Information, p. 18). In the course of the studies, the complex Pb·(1·N2O3) was also investigated (see Supporting Information, pp. 35–36) and showed 1H–207Pb spin– spin couplings. It was, however, less suited for the present purposes, since the coupling constants were significantly smaller.
Reaction of dialdehyde 2 with the diamine N2O3—formation +2]-macrocycle 22·(N2O3)2 of the [2+ The dialdehyde 2 and the diamine N2O3 (1 equiv each) were dissolved in CD3CN/CDCl3 1:1 at 10 mm concentration in an NMR tube and left to equilibrate at 60 8C. The reaction mixture was then analysed by 1D- and 2D-NMR spectroscopy as well as by MS (MALDI and ESI; see Supporting Information, pp. 13–14) revealing the formation of a [2+ +2]-macrocycle. Although the reaction of dialdehyde 2 with other diamines was investigated (see also references [14b,d]), we focus here on this particular case, which gave the best results for the present purposes. The formation and solid-state molecular structure of the related compound 22·(N2O)2 have already been reported previously (see also Supporting Information, pp. 9–10).[20]
Reaction of dialdehyde 2 with the diamine N2O3 in presence of cadmium ions—metal-templated formation of the macrocyclic complex Cd·(2·N2O3). A mixture of dialdehyde 2, diamine N2O3 and cadmium triflate (1 equiv each) dissolved in CD3CN/CDCl3 1:1 at 10 mm concentration led to the formation of the bis-imine [1+ +1]-macrocycle Cd·(2·N2O3).[22] This macrocyclic complex was characterised by 1D- and 2D-NMR spectroscopy as well as by MS (MALDI and ESI; see Supporting Information, pp. 19–21) and by determination of its solid-state molecular structure (see Supporting Information, p. 21). The solid-state structure shows that the Cd2 + cation is bound to one counterion and two water molecules and not to the oxygen atoms of the diamine component, which is too distant for a direct coordination. Imine-proton– Chem. Eur. J. 2015, 21, 10070 – 10081
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Cd2 + -cation spin–spin splittings are observed in the 1H NMR spectrum (Figure 4; top). The reaction of the dialdehyde 2 and the diamine N2O3 (1 equiv each) was also conducted using only 0.5 equivalents of Cd(OTf)2 in CD3CN/CDCl3 1:1 at 10 mm concentration. The mixture was heated at 60 8C and showed sets of sharp 1H NMR signals corresponding to the Cd·[22·(N2O3)2]
Figure 4. 1H NMR spectra of the complexes Cd·(2·N2O3) and Cd·[22·(N2O3)2] (see Supporting Information, pp. 19-24 for more details). The broad background, observed only after removal of half of the metal ion (bottom spectrum), disappears after completing the titration and removing all the cation (see also text).
(Figure 4; bottom, see also 2D-NMR data in the Supporting Information, pp. 22–24). A broad background is also observed, which is only present after removal of half of the cation, but it disappears at the termination of the titration, on removal of all the cation after addition of hexacyclen. Thus, the broad band could be due to the presence of transient species, notably oligomers, formed from the half amount of reactive free macrocycle generated in the intermediate state and/or that the recondensation of the oligomers to the [2+ +2]-macrocycle is very slow. +2]-complex As efforts to obtain a single crystal of this [2+ failed, a modelling of its equilibrium geometry was pursued using DFT-calculations (B3LYP/6-31G*). The structure calculated presents the expected pattern of a hexacoordinated cation with the imine nitrogen atoms connected by the ligand chains, resulting in a twisted macrocyclic chain centered on Cd (see Supporting Information, p. 24). The same pattern of resolved aliphatic peaks in the 1H NMR spectrum was observed for the dinuclear Cd complex of the [2+ +2]-macrocycle formed by the shorter diamine N2O2 and a similar structure was modelled by DFT (see Supporting Information, pp. 25–27). In order to gain further information about the structures of Cd·[22·(N2O3)2] and Cd·(2·N2O3), 1D-113Cd and 2D-1H–113CdHMQC NMR experiments were performed.[23] Such studies can not only show cross-correlations between the strongly coupled imine protons and the Cd center, but also give indications about the positioning of the oxo–ethylene bridges and corrob-
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Full Paper Generation and behaviour of the strained macrocycles 1·N2O and 2·N2O3 The data presented above set the stage for a study of the features and the fate of the strained [1+ +1]-macrocycles that may be generated upon removal of the stabilizing metal cation by a competing ligand. The high-energy states result from the presence in the free macrocyclic ligands thus obtained of subunit conformations and orientations that do not correspond to their minimum energy form, when not constrained by a macrocyclic structure. One may expect that such out-of-equilibrium entities 1 113 113 Figure 5. H– Cd-HMQC (top) and Cd NMR (bottom) data for the structural investigation of the complexes would present an increased Cd·(2·N2O3) and Cd·[22·(N2O3)2]. strain-induced reactivity induced by their strong tendency to find a way to relax to their lowest energy equilibrium state/strucorate the computed structural proposal for Cd·[22·(N2O3)2] (see ture. Figure 5 and Supporting Information, p. 24). The differences of To investigate such features, we formed the related comchemical shift in the 113Cd NMR spectrum of Cd·(2·N2O3) plexes Cd·(1·N2O), Cd·(2·N2O3) and Cd·[22·(N2O3)2], and studied (¢658.04 ppm) and Cd·[22·(N2O3)2] (¢489.54 ppm), both refertheir behaviour after removal of the metal cation by treatment enced to Cd(OTf)2, are a point of structural argumentation as of the reaction mixtures with hexacyclen. As previously stated, well (Figure 5). As has been reported and discussed,[24] oxygenthe use of Cd2 + as the complexed metal ion brings the advantcontaining ligands, such as certain cryptates, cause an upfield 113 shift for Cd, due to shielding effects. The multiple oxygenage of the appearance of splittings due to 1H–113Cd spin–spin coupling in the 1H NMR spectrum (see Figure 3), which are containing [2.2.2]-cryptand was shown to exhibit a shift of [24b] ¢62 ppm, a valuable indication to determine whether the Cd ion has whereas complexes with nitrogen-containing libeen removed from the complex. It is important to stress that gands, such as bipyridine, were located in a range around the water content of the medium (NMR solvent) plays a crucial + 240 ppm,[25] (in both cases referenced against Cd(ClO4)2). role in the transformations to be examined, since water is Considering the proposed structure of Cd·[22·(N2O3)2], the coneeded for their occurrence through ring opening by hydrolyordination to six nitrogen sites as the main coordinating elesis and ring-size redistribution. ments goes in line with these studies. Furthermore such a difference in NMR shift might be due to the difference in coordination geometry. Whereas Cd·[22·(N2O3)2] can potentially adopt Macrocyclic compounds of dialdehyde 1 a closely octahedral geometry, the complex Cd·(2·N2O3) on the In a first series of experiments, addition of hexacyclen (ca. other hand has a much more distorted structure using differ1.5 equiv) to a solution of separately prepared Cd·(1·N2O) in ent coordination sites, which could also account for the pronounced difference in chemical shift. A similarly distorted CD3CN/CDCl3 1:1 at 10 mm concentration led to the rapid disstructure may be found in a recently reported, but dinuclear, appearance of the H–Cd splittings, indicating that the coordicopper(I) complex.[26] nated metal ion had been quickly removed from the macrocyclic complex. The resulting strained macrocycle 1·N2O generatThe reaction of the shorter diamines N2O and N2O2 with diaed could be observed briefly and then its progressive transforldehyde 2 was also studied (see Supporting Information, mation followed, ending up in the final product identified as pp. 9–10 and pp. 25–27). In both cases the [2+ +2]-macrocycle the [2+ was formed in the free, non-complexed state as well as in the +2]-macrocycle 12·(N2O)2 (Scheme 2 and Figure 6). complexed form with CdII and AgI cations. The solid-state moIt must be stressed that the rate of decay of the initial complex changed from experiment to experiment (from about 6 h lecular structure could be determined for the dinuclear AgI as in Figure 6 to usually less than 15 min), as it was difficult to complex Ag2·[22·(N2O2)2], bearing a molecule of 4-dimethylamicontrol the very small amount of residual water present in the nopyridine coordinated to each Ag center (see the Supporting solution. However, the start and end points of the different Information for details, p. 32). Data for the [2+ +2]-macrocycle runs were well reproducible. Remarkably, transient aldehyde formed with the diamine N2O are also given in the Supporting species were seen to form and then to disappear again at Information. Chem. Eur. J. 2015, 21, 10070 – 10081
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Scheme 2. Representation of the conversion of the [1+ +1]-complex Cd·(1·N2O) into the final strain-released state, the [2+ +2]-macrocycle 12·(N2O)2 (top),via +1]-macrocycle 1·N2O followed by ring opening to transient non-cyclic amino–aldehyde species (bottom), cation removal to give the transient strained [1+ which then undergo recondensation.
open-chain intermediates containing imine and aldehyde +2]groups which thereafter re-condense to give the final [2+ macrocycle 12·(N2O)2. In fact, two sets of aldehyde proton signals were observed, one being much more intense than the other one, indicating that there were at least two different intermediates and that these were undergoing reaction at different rates. It can also be seen that the imine proton signals broaden and shift as the aldehyde signals appear, and then sharpen again with the disappearance of the aldehydes and the formation of the final dimeric macrocycle, indicating that some kind of exchange/rate process was taking place in the intermediate phase. The macrocycles and complexes of dialdehyde 1 formed with the longer diamines N2O2 and N2O3 were prepared, but their behaviour in decay studies was not pursued in detail as it appeared less informative for the present purposes (for details, see Supporting Information pp. 7–8 and pp. 37-42). Macrocyclic compounds of dialdehyde 2
Figure 6. Evolution of the 1H NMR spectrum of the [1+ +1]-complex Cd·(1·N2O) after removal of the Cd cation by addition of 1.5 equivalents of hexacyclen as a function of time from top to bottom. The ¢CH=O proton signals correspond to the formation of transient open-chain amino–aldehyde intermediates (see Figure 7). The shift of the imine ¢CH=N signals is discussed below.
completion of the transformation. The changes observed may thus be attributed to progressive hydrolysis of the imine bonds by the residual water present in the solution, leading to Chem. Eur. J. 2015, 21, 10070 – 10081
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To further investigate the strain-induced reactivity, the behaviour of the complex Cd·(2·N2O3) was also examined. It was expected to connect the strained [1+ +1]-adduct with the relaxed state, the [2+ +2]-adduct (and/or eventually oligomers). Addition of 1.5 equivalents of hexacyclen led to the complete removal of the Cd2 + cation from the macrocyclic complex Cd·(2·N2O3) and to the formation of a new species as observed in the 1 H NMR spectra (Figure 7; top). This species did not present any 1H–113Cd splittings, indicating that it was not complexed to a Cd2 + cation and is thus expected to be the strained free [1+ +1]-macrocycle 2·N2O3. It decayed with a half-life of about
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Figure 7. Top: Evolution of the 1H NMR spectrum of the [1+ +1]-complex Cd·(2·N2O3) after removal of the Cd cation by addition of 1.5 equivalents of hexacyclen as a function of time from top to bottom: at t = 0, after 2, 12 and 22 min, 3.5 h and overnight respectively (from top to bottom). Bottom: +1]-complex Cd·(2·N2O3) after 2 h 10 min of treatment with a) the [1+ 0.5 equiv of hexacyclen b) leading to transient species Cd·[22·(N2O3)2] after 3 h 20 min, c) which then converts into 22·(N2O3)2 d) 10 min after addition of a further 1.0 equivalents of hexacyclen. e) and f) Separately prepared reference samples of 22·(N2O3)2 and Cd·[22·(N2O3)2], respectively (concentrations are 10 mm in all cases). The strong aliphatic signals in the 2.5–3.0 ppm region are due to hexacyclen. For the broad background in spectrum f), see comments for Figure 4 in text. One may note that when the cadmium cations are removed from the macrocycle Cd·(1·N2O), only a weak shift of the NMR signal of the CH=N proton is observed (see Figure 6). The larger shift of 0.3 ppm (see top of this figure) observed in the present case of the macrocycle Cd·(2·N2O3) could be due to the greater flexibility of the diamine chain and the resulting possibility of some fast conformational change.
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12 3 min into the [2+ +2]-macrocycle 22·(N2O3)2, after appearance and disappearance of intermediates visible in the 1H NMR spectra. These intermediates consisted presumably in openchain compounds with aldehyde groups (visible by very weak signals between 10.0 and 10.2 ppm), which then underwent recondensation to give the relaxed [2+ +2]-macrocycle 22·(N2O3)2, in a way similar to the behaviour observed for the Cd·(1·N2O) complex (see Scheme 2). Integration of the water proton signals indicated that these processes took place in the presence of 4 equivalents of water with respect to the starting complex. It should be noted, that the [2+ +2]-macrocycle 22·(N2O3)2 is formed as a main species (estimated to amount to about 70 % from 1H NMR), alongside secondary products, possibly oligomeric materials. Thus, the behaviour of this system (2 + N2O3) is not as clear-cut as the previous one, but is nevertheless informative for the present purposes. In another set of experiments, taking into account the results on the formation of the [2+ +2]-complexes (see above), 0.5 equivalents of hexacyclen were added to a sample of Cd·(2·N2O3) (Figure 7; bottom). Roughly 3 h after the addition and heating to 60 8C to ensure completion of the reaction, the +2]-complex Cd·[22·(N2O3)2] had formed, alongside other sec[2+ ondary products. When the reaction was conducted at room temperature this complex was not obtained within the same time period, as one might expect considering a slower rate for the ring opening and recombination involved in the process. The transformation of one species into the other one could also be followed by examination of the 1H–113Cd splittings, which decreased from 21.0 Hz for Cd·(2·N2O3) to 17.6 Hz for Cd·[22·(N2O3)2]. After the further addition of 1.0 equivalents of hexacyclen, the rapid appearance, within 2 min, of a species identical to a separately prepared sample of 22·(N2O3)2 was observed (again in an purity of about 70 %). The first transformation may be considered to involve the sequence (Scheme 3): 1) initial generation of 0.5 equivalents of strain-free 2·N2O3 macrocycle from Cd·(2·N2O3) by cation removal with 0.5 equiv+2]-macrocycle; alents hexacyclen; 2) 2·N2O3 then gives the [2+ 3) this marcocycle then acts as decomplexing agent towards half of the remaining 0.5 equivalents of Cd·(2·N2O3); 4) the thus progressively liberated free 2·N2O3 in turn gives [2+ +2]macrocycle; 5) the macrocycle then reacts with the remaining Cd·(2·N2O3) complex, resulting in the full transformation of Cd·(2·N2O3) into Cd·[22·(N2O3)2]. This behaviour is in line with the appearance of an operative strain-activated state, that is, the formation of the 2·N2O3 macrocycle. The second transformation is a simple decomplexation of Cd·[22·(N2O3)2] on addition of more hexacyclen to give the uncomplexed [2+ +2]-macrocycle 22·(N2O3)2. With the diamine N2O2 no [1+ +1]-macrocycle is formed, neither with nor without metal, but the [2+ +2]-macrocycle is directly obtained. N2O2 appears to be too short to form a [1+ +1]macrocyclic complex. The same also holds for the N2O diamine. Only the cadmium complex of the [2+ +2]-macrocycle 22·(N2O2)2 could be identified.
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Scheme 3. Structural representation of the transition of the [1+ +1]-complex Cd·(2·N2O3) through the respective intermediates Cd·[22·(N2O3)2] and 2·N2O3 to reach the final common strain released state 22·(N2O3)2.
Theoretical evaluation of the energetics of the structures 1·N2O and 2·N2O3 and of their strain-induced transformations To gain insight into the energetics of the transformations described above, and in particular into the occurrence of strain-induced reactivity, Hartree–Fock calculations were performed on the molecular structures of the free macrocyclic ligands 1·N2O and 2·N2O3. The high reactivity of these species is reflected in their short lifetime in the conditions of the experiments and the formation of thermodynamically stable relaxed derivatives. Hartree–Fock (HF; 6-311 + G**) calculations have been performed on model structures presenting the main structural features of these macrocycles.[27] These incorporate in particular subunits reminiscent of the cisoid (c) f-NCCN- = 08 and transoid (t) f-NCCN- = 1808 conformations of 2,2’-bipyridine, for which computational results have indicated that the former is about 30 kJ mol¢1 less stable than the latter, representing respective global maxima and minima.[12d] The reason for these energetic differences can be found in manifold factors, such as lone pair repulsions between nitrogen atoms (destabilizing the c-form), steric repulsions between protons (destabilizing the c-form), pconjugation effects of the aromatic systems (destabilizing outof-plane rotations), and attractive interactions between aromatic protons and N-lone pairs (stabilizing the t-form). One may consider that similar effects influence the reactivity of the systems discussed in this work. To simplify these and reduce computational cost, the chains of the diimine linkers in the macrocycles 1·N2O and 2·N2O3 were replaced by methyl groups to give the model compounds 1·(NMe)2 and 2·(NMe)2. HF calculations were performed on two rotationally restricted rotamers of 2·(NMe)2 corresponding to N-C-C-N dihedral angles of 08 and 1808 (Scheme 4). Therefore, the structures of 1·(NMe)2 and 2·(NMe)2 were maintained in planar form. For 2·(NMe)2, the energy difference was found to be about 5.1 kcal mol¢1 between the tt and ct forms and 6.9 kcal mol¢1 between the ct and the cc forms, adding up to a total energy difference Chem. Eur. J. 2015, 21, 10070 – 10081
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Scheme 4. Rotamer energies for 2·(NMe)2.The arrows indicate cisoid conformations about N-C-C-N bonds, stressing the lone pair-repulsions.
of 12.0 kcal mol¢1, to be compared to 12.1 kcal mol¢1 directly between the cc and tt forms. These results show that the computed energy differences between the structures add up satisfactorily. They also indicate that the removal of the metal cation from the Cd·(2·N2O3) complex, in which the ligand conformation is stabilised by the binding of the cation, liberates a species of very significant strain energy that strongly enforces the molecule to relax and thus may be expected to cause a marked ring strain-induced reactivity enhancement, driving the rapid cleavage of the ring and the recombination of the fragments generated into the relaxed dimeric [2+ +2]-macrocycle 22·(N2O3)2. Thus, the diamine N2O3 condenses with the 2,6pyridinedicarboxaldehyde 2 in the W form to give the strainfree [2+ +2]-macrocycle. The model compound 1·(NMe)2 gave results for the relative energies of the different conformations that were comparable to those computed for 2·(NMe)2 (Scheme 5). Considering that the conformations of the core tri-nitrogen unit of 1·(NMe)2 have features similar to those computed for 2·(NMe)2, computations were performed only on the U shape cisoid–cisoid form and on the two additional cisoid–transoid orientations of the imine groups for 1·(NMe)2. Since the dialdehyde 1 is non-symmetric, there are of course two different “mixed” states with f-
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Full Paper In the present case, the transient free macrocycles 1·N2O and 2·N2O3 rapidly decay and form the corresponding [2+ +2]-macrocycles 12·(N2O)2 and 22·(N2O3)2 via open-chain (aldehyde–amine) intermediates (see above and Figures 6 and 7, and Schemes 2 and 3). It is also probable, that the origin of reactivity of the [1+ +1]macrocycles also lies in their accumulated strain energy. Indeed, the reactivity of the imine bonds would be enhanced in the free macrocycles 1·N2O and 2·N2O3 by straining of the imine C(sp2)= N(sp2) unit, increasing its propensity to relax to a C(sp3)¢N(sp3) state by the addition of a nucleophile, namely water. Consequently, the hydrolysis of the imine functional group is facilitated, generating an open-chain intermediate, which subsequently can recondense to give the signifiScheme 5. Rotamer energies 1·(NMe)2. The arrows indicate cisoid conformations about N-C-C-N bonds, stressing the lone pair-repulsions. +2]-macrocantly less strained [2+ cycles or other cyclic and noncyclic oligomeric entities. The increased reactivity of the [1+ +1]-macrocycles is also highlighted NCCN- = 0–1808 and f-NCCN- = 180–08 respectively. The first transby the fact that the final compound obtained is the [2+ oid to cisoid change resulted in the energy differences DE180– +2]-mac¢1 rocycle, meaning that the former opens up by dissociation of and DE180–1808!0–1808 = 6.8 kcal mol¢1, 1808!180–08 = 5.1 kcal mol the strained imine bonds and then recondenses to the compawhereas the second cisoid form gave DE180–08!0–08 = 10.5 kcal ratively unstrained imine groups of the latter, rather than remol¢1 and DE0–1808!0–08 = 8.8 kcal mol¢1. More details about the maining open chain. relative energies of the different conformations are representIndications in favour of an increased reactivity of the C=N ed in Scheme 5. Overall, the results obtained for both cases unit by strain-induced distortion of the C=N¢R angle from the studied here are in line with the reported computations on the formal unstrained 1208 towards a larger angle may be gained conformations of bipyridine itself.[12] from theoretical studies of in-plane nitrogen inversion of Since the present calculations concern model compounds, imines.[28] Indeed, ab initio computations on the in-plane nitrothey omit additional effects that may be present in the ringgen inversion of imines, show that the change in electronic closed structure of the macrocycles incorporating the nitrogen charge distribution from the bent ground state to the linear containing cores of the models 1·(NMe)2 and 2·(NMe)2, mean+),N(¢) polarity, ing that the actual energy differences of the different forms of transition state leads to an increase in the C(+ thus facilitating reaction of a nucleophile at the carbon center the closed macrocycles could even be significantly higher than of the imine group. In line with these considerations, the signal those obtained here. of the imine proton is at 8.45 ppm for the demetallated [1+ +1]macrocycle 2·N2O3 and at 8.30 ppm for the [2+ +2]-macrocycle 22·(N2O3)2 (Figure 7). This upfield shift of about 0.15 ppm beOrigin of the enhanced reactivity of the macrocycles 1·N2O tween the strained [1+ +1]-macrocycle and the resting [2+ +2]and 2·N2O3 macrocycle fits with an increase in positive charge on the carbon site and thus with a distortion of the C=N¢C angle toWe showed previously[10] that steric strain caused by CH3/CH3 wards linearity. interaction on introduction of methyl groups at the C and N One may also note that in the strained [1+ sites at the ends of the C=N¯¢N¯ unit of the hydrazone C +1]-macrocycles (Figure 1) caused a marked twist around the N¢N bond, thus distortion/rotation of the C¢CH=N¢ group out of the pyridine decreasing conjugation within the C=N¯¢N¯ fragment and leadplane should both deconjugate it from the pyridine group and ing to a significant increase of the reactivity of the hydrazone change its orientation with respect to the pyridyl nitrogen, bond. As a consequence, constitutional dynamic exchange repossibly causing some destabilisation. Somewhat related is the actions were markedly facilitated. fact that pyridine-2-aldehyde forms a larger amount of imine Chem. Eur. J. 2015, 21, 10070 – 10081
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Full Paper (61 %) with isopentylamine than benzaldehyde (20 %).[29] Both of the strain-induced structural effects evoked, that is, in-plane distorsion and out-of plane rotation, lead in the direction of a less stable/more reactive imine group. Thus, the origin of the strain-enhanced reactivity observed herein for the [1+ +1]-macrocycles 12·(N2O)2 and 22·(N2O3)2 can be manifold, with contributions from various effects resulting from strain-induced structural distorsion. From another point of view of much significance with respect to the perspectives of coupling constitutional dynamic chemistry to out-of-equilibrium and dissipative processes, one notes that the strained [1+ +1]-macrocycles 1·N2O and 2·N2O3 represent kinetically trapped out-of-equilibrium, high-energy states that progressively relax to the corresponding thermody+2]-macronamically stable states composed of the derived [2+ cycles and eventually oligomeric entities. Thus, the strain-enhanced reactivity observed is driven by an out-of-equilibrium to equilibrium conversion process. For clarity, the full set of transformations is summarised in Scheme 6 for the specific case involving the 1, N2O and Cd2 + components.
Cd·(2·N2O3) here) the macrocyclic ligand is maintained in a markedly strained conformation by the coordination forces of the metal cation. 2) The removal of the coordinated metal cation from these complexes generates highly strain-free macrocycles (e.g., 1·N2O and 2·N2O3), which incorporate various structural deformations with respect to their preferred, relaxed state. These are very reactive and release their strain by undergoing ring opening through rapid hydrolysis by trace amounts of water in the reaction medium. 3) These reactive metal-free macrocycle intermediates (e.g., 1·N2O and 2·N2O3) can be considered as constituting an out-of-equilibrium state, which progressively attains equilibrium by converting into a thermodynamically stable state, comprising the relaxed [2+ +2]-macrocycles (e.g., 12·(N2O)2 and 22·(N2O3)2) and eventually oligomeric entities. Such out-of-equilibrium states may be generated in various ways such as substrate binding (e.g., metal cation coordination here), photoactivation, phase separation[30,31] and so forth, and harnessed to drive chemical transformations.
Experimental Section Typical experiment: The dialdehyde and the corresponding metal triflate (considering a final concentration of 10 mm) were taken up in 500 mL of CDCl3/CD3CN 1:1, mixed and transferred into an NMR tube. Subsequently a solution of the corresponding diamine in 200 mL (10 mm in CDCl3/CD3CN 1:1, vide supra) was added to the NMR tube, the sample thoroughly mixed and the formation of the corresponding compounds was followed by NMR spectroscopy after equilibrating at room temperature or 60 8C. For the removal of the cation from the complexes, the corresponding amount of the hexacyclen (e.g., 0.5 or 1.5 equiv) was dissolved in 100 mL of the same solvent, added to the NMR-tube and the course of the reaction followed directly.
Scheme 6. Representation of the set of transformations undergone by the dynamic covalent system comprising the components 1, N2O and Cd2 + . It proceeds via the generation of a high energy out-of-equilibrium state, the transient free macrocycle 1·N2O (bottom center) presenting strain-induced reactivity and involves constitutional switching between a “metallo-macrocycle state” stabilised by metal cation coordination (right) and an uncomplexed “resting state” (left) in response to shape change of component 1 on cation biding and removal.
General descriptions and characterisations: See Supporting Information. CCDC 1055945 and 1055946 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
Conclusion The results reported above highlight the operation of structural features of various types that impose a high energy state on a chemical entity and thus enforce an increase in reactivity. They lead to several conclusions that may be summarised as follows. 1) In the well-known bis-imine macrocyclic complexes obtained by templated synthesis (e.g., Cd·(1·N2O) and Chem. Eur. J. 2015, 21, 10070 – 10081
Details for NMR spectroscopy: For NMR spectra recorded in CDCl3/CD3CN, the CH3CN peak was chosen for calibration. The NMR solvents were filtered as received (Sigma–Aldrich or EurisoTop) through a pad of Al2O3 and subsequently stored over freshly activated molecular sieves (3 æ) under exclusion of light.
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We thank the NMR spectroscopy and mass spectrometry services of the Universit¦ de Strasbourg. We thank the ANR (2010 BLAN-717-1 grant) and the ERC (Advanced Research Grant SUPRADAPT 290585) for financial support. G.V. thanks the MinistÀre de l’Enseignement Sup¦rieur et de la Recherche for a doctoral fellowship. L.R. thanks the Wissenschaftsportal—Franzçsische Botschaft in Deutschland for a post-doctoral fellowship. We thank Dr. Jean-Louis Schmitt for his valuable help with
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Full Paper NMR measurements and valuable discussions and assistance. We would like to express our gratitude to Dr. Gustavo Pierdominici-Sottile and Dr. Ezequiel Juritz from the National University of Quilmes (Argentina) for their valuable help with the computational studies. Keywords: dynamic covalent chemistry (DCC) · imines · macrocycles · out-of-equilibrium · strained molecules [1] a) A. von Baeyer, Ber. Dtsch. Chem. Ges. 1885, 18, 2269 – 2281; b) K. B. Wiberg, Angew. Chem. Int. Ed. Engl. 1986, 25, 312 – 322; Angew. Chem. 1986, 98, 312 – 322. [2] The term entasis was first used in the context of metalloenzymes, see for instance: B. L. Vallee, R. J. P. Williams, Proc. Natl. Acad. Sci. USA 1968, 59, 498 – 505. [3] a) H. Sachse, Ber. Dtsch. Chem. Ges. 1890, 23, 1363 – 1370; b) H. Sachse, Z. Phys. Chem. 1892, 10, 201 – 241; c) H. Sachse, Z. Phys. Chem. 1893, 11, 185 – 219. [4] See for instance deformations due to diaxial methyl–methyl interactions on cyclohexane rings in triterpenes: a) J.-M. Lehn, J. Levisalles, G. Ourisson, Tetrahedron Lett. 1961, 2, 682 – 686; b) J.-M. Lehn, J. Levisalles, G. Ourisson, Bull. Soc. Chim. Fr. 1963, 1096 – 1101. [5] E. L. Eliel, S. H. Willen, Stereochemistry of Organic Compounds, Wiley, New York, 1994. [6] a) K. Tani, B. M. Stoltz, Nature 2006, 441, 731 – 734; b) J. Clayden, Nature 2012, 481, 274 – 275; c) J. Clayden, W. J. Moran, Angew. Chem. Int. Ed. 2006, 45, 7118 – 7120; Angew. Chem. 2006, 118, 7276 – 7278. [7] A. J. Kirby, I. V. Komarov, P. D. Wothers, N. Feeder, Angew. Chem. Int. Ed. 1998, 37, 785 – 786; Angew. Chem. 1998, 110, 830 – 831. [8] a) V. Somayaji, R. S. Brown, J. Org. Chem. 1986, 51, 2676 – 2686; b) H. Slebocka-Tilk, R. S. Brown, J. Org. Chem. 1987, 52, 805 – 808; c) A. J. Bennet, Q. P. Wang, H. Slebocka-Tilk, V. Somayaji, R. S. Brown, B. D. Santarsiero, J. Am. Chem. Soc. 1990, 112, 6383 – 6385; d) J. I. Mujika, J. M. Mercero, X. Lopez, J. Am. Chem. Soc. 2005, 127, 4445 – 4453; e) B. Wang, Z. Cao, Chem. Eur. J. 2011, 17, 11919 – 11929. [9] J. Y. W. Mak, R. H. Pouwer, C. M. Williams, Angew. Chem. Int. Ed. 2014, 53, 13664 – 13688; Angew. Chem. 2014, 126, 13882 – 13906. [10] G. Vantomme, S. Jiang, J.-M. Lehn, J. Am. Chem. Soc. 2014, 136, 9509 – 9518. [11] The corresponding arrangement is reminiscent of a diaxial methyl – methyl interaction on a cyclohexane ring, which amounts to about 4.0 Kcal mol¢1; see: N. L. Allinger, M. A Miller, J. Am. Chem. Soc. 1961, 83, 2145 – 2146. [12] Calculations yield a preference of 2,2’-bipyridine for the transoid with respect to cisoid form by about 25–30 kJ mol¢1: a) S. T. Howard, J. Am. Chem. Soc. 1996, 118, 10269 – 10274; b) A. Gçller, U.-W. Grummt, Chem. Phys. Lett. 2000, 321, 399 – 405; c) G. Corongiu, P. Nava, Int. J. Quantum Chem. 2003, 93, 395 – 405. For structural and spectroscopic data, see: d) L. L. Merritt Jr., E. D. Schroeder, Acta Crystallogr. 1956, 9, 801 – 804; e) F. Bertinotti, A. M. Liquori, R. Pirisi, Gazz. Chim. Ital. 1956, 86, 893 – 898; f) K. Nakamoto, J. Phys. Chem. 1960, 64, 1420 – 1425; g) S. Castellano, H. Gunther, S. Ebersole, J. Phys. Chem. 1965, 69, 4166 – 4176; h) I. C. Calder, T. M. Spotswood, C. I. Tanzer, Aust. J. Chem. 1967, 20, 1195 – 1212; i) V. Barone, C. Minichino, S. Fliszar, N. Russo, Can. J. Chem. 1988, 66, 1313 – 1317; j) C. Jaime, J. Font, J. Org. Chem. 1990, 55, 2637 – 2644. [13] a) G. S. Hanan, J.-M. Lehn, N. Kyristakas, J. Fischer, J. Chem. Soc. Chem. Commun. 1995, 765 – 766; b) M. Ohkita, J.-M. Lehn, G. Baum, D. Fenske, Chem. Eur. J. 1999, 5, 3471 – 3481. [14] a) M. Barboiu, J.-M. Lehn, Proc. Natl. Acad. Sci. USA 2002, 99, 5201 – 5206; b) M. Barboiu, G. Vaughan, N. Kyritsakas, J.-M. Lehn, Chem. Eur. J. 2003, 9, 763 – 769; c) A.-M. Stadler, J. Ramirez, J.-M. Lehn, Chem. Eur. J. 2010, 16, 5369 – 5378; d) A.-M. Stadler, J.-M. Lehn, J. Am. Chem. Soc. 2014, 136, 3400 – 3409. [15] a) B. Dietrich, P. Viout, J.-M. Lehn, Macrocyclic Chemistry: Aspects of Organic and Inorganic Supramolecular Chemistry, Wiley-VCH, Weinheim, 1993; b) L. A. Wessjohann, D. G. Rivera, F. Leûn, Org. Lett. 2007, 9, 4733 – 4736; c) D. B. Amabilino, J. F. Stoddart, Chem. Rev. 1995, 95, 2725 – 2828; d) P. T. Glink, A. I. Oliva, J. F. Stoddart, A. J. P. White, D. J. WilChem. Eur. J. 2015, 21, 10070 – 10081
www.chemeurj.org
[16] [17]
[18]
[19]
[20] [21] [22]
[23] [24]
[25] [26] [27]
[28]
10080
liams, Angew. Chem. Int. Ed. 2001, 40, 1870 – 1875; Angew. Chem. 2001, 113, 1922 – 1927; e) B. H. Northrop, F. Aricû, N. Tangchiavang, J. D. Badjic´, J. F. Stoddart, Org. Lett. 2006, 8, 3899 – 3902; f) A. R. Williams, B. H. Northrop, T. Chang, J. F. Stoddart, A. J. P. White, D. J. Williams, Angew. Chem. Int. Ed. 2006, 45, 6665 – 6669; Angew. Chem. 2006, 118, 6817 – 6821; g) I. T. Harrison, S. Harrison, J. Am. Chem. Soc. 1967, 89, 5723 – 5724. N. F. Curtis, Coord. Chem. Rev. 1968, 3, 3 – 47. a) J.-M. Lehn, Chem. Eur. J. 1999, 5, 2455 – 2463; b) S. J. Rowan, S. J. Cantrill, G. R. Cousins, J. K. M. Sanders, J. F. Stoddart, Angew. Chem. Int. Ed. 2002, 41, 898 – 952; Angew. Chem. 2002, 114, 938 – 993; c) P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor, J. K. M. Sanders, S. Otto, Chem. Rev. 2006, 106, 3652 – 3711; d) J.-M. Lehn, Chem. Soc. Rev. 2007, 36, 151 – 160; e) S. Ladame, Org. Biomol. Chem. 2008, 6, 219 – 226; f) B. L. Miller Dynamic Combinatorial Chemistry, Wiley, Chichester, 2010; g) J. N. H. Reek, S. Otto, Dynamic Combinatorial Chemistry, Wiley-VCH, Weinheim, 2010; h) R. A. R. Hunt, S. Otto, Chem. Commun. 2011, 47, 847 – 855; i) M. E. Belowich, J. F. Stoddart, Chem. Soc. Rev. 2012, 41, 2003 – 2024; j) J.-M. Lehn, M. Barboiu, Topics Curr. Chem 2012, 322, 1 – 32; k) J.-M. Lehn, Angew. Chem. Int. Ed. 2013, 52, 2836 – 2850; Angew. Chem. 2013, 125, 2906 – 2921. a) S. Ulrich, E. Buhler, J.-M. Lehn, New J. Chem. 2009, 33, 271 – 292; b) S. Ulrich, J.-M. Lehn, Angew. Chem. Int. Ed. 2008, 47, 2240 – 2243; Angew. Chem. 2008, 120, 2272 – 2275; c) S. Ulrich, J.-M. Lehn, J. Am. Chem. Soc. 2009, 131, 5546 – 5559. The case of N2O2 was studied as well and gave similar and conclusive results but the SIR behaviour was more difficult to analyse (see Supporting Information, pp. 7,11,25 and 37). P. C. Haussmann, S. I. Khan, J. F. Stoddart, J. Org. Chem. 2007, 72, 6708 – 6713. P. D. Ellis, Science 1983, 221, 1141 – 1146. a) D. E. Fenton, R. Leonaldi, Inorg. Chim. Acta 1981, 55, L51 – L53; b) A. Freira, R. Bastida, L. Valencia, A. Macas, C. Lodeiro, H. Adams, Inorg. Chim. Acta 2006, 359, 2383 – 2394; c) H. Adams, N. A. Bailey, D. E. Fenton, Y.-S. Ho, Inorg. Chim. Acta 1993, 212, 65 – 68; d) R. Menif, D. Chen, A. E. Martell, Inorg. Chem. 1989, 28, 4633 – 4639. D. Live, I. M. Armitage, D. C. Dalgarno, D. Cowburn, J. Am. Chem. Soc. 1985, 107, 1775 – 1777. a) P. S. Marchetti, S. Bank, T. W. Bell, M. A. Kennedy, P. D. Ellis, J. Am. Chem. Soc. 1989, 111, 2063 – 2066; b) P. G. Mennitt, M. P. Shatlock, V. J. Bartuska, G. E. Maciel, J. Phys. Chem. 1981, 85, 2087 – 2091. M. Munataka, S. Kitagawa, F. Yagi, Inorg. Chem. 1986, 25, 964 – 970. M. Hutin, G. Bernardinelli, J. R. Nitschke, Proc. Natl. Acad. Sci. USA 2006, 103, 17655 – 17660. a) The molecular conformations of the macrocycle-fragments were investigated by computational approaches, using the Spartan ’10[27b] software package from Wavefunction Inc. (Scheme 4; standard Windows personal computer) or Gaussian 09[27c] (Scheme 5; computation facility in Quilmes, Argentina) respectively. The calculations were performed using Hartree–Fock methods with 6-311 + G** basis sets. Overall planarity and geometry was conserved, and free energies calculated and compared. Structural optimisations for Cd·[22·(N2O2)2] and Cd·[22·(N2O3)2] were carried out on a DFT-level (gas-phase), using RB3LYP-6-31-G* with an overall charge of + 2; b) Spartan ’10, Wavefunction, Inc., Irvine, CA; c) Gaussian 09, Revision A.02-SMP, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, ©. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc. Wallingford CT, 2009. a) J.-M. Lehn, B. Munsch, P. Millie, Theor. Chim. Acta. 1970, 16, 351 – 372; b) J. Glvez, A. Guirado, J. Comput. Chem. 2010, 31, 520 – 531 and private communication. Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Full Paper [29] P. Kovarˇcˇek, J.-M. Lehn, J. Am. Chem. Soc. 2012, 134, 9446 – 9455 and Table 1 therein. [30] N. Hafezi, J.-M. Lehn, J. Am. Chem. Soc. 2012, 134, 12861 – 12868.
[31] J.-M. Lehn, Angew. Chem. Int. Ed. 2015, 54, 3276 – 3289; Angew. Chem. 2015, 127, 3326 – 3340. Received: March 26, 2015 Published online on June 8, 2015
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