Conformational equilibrium in supramolecular chemistry: Dibutyltriuret case

The association of substituted benzoates and naphthyridine dianions was used to study the complexation of dibutyltriuret. The title molecule is the simplest molecule able to form two intramolecular hydrogen bonds. The naphthyridine salt was used to break two intramolecular hydrogen bonds at a time while with the use of substituted benzoates the systematic approach to study association was achieved. Both, titrations and variable temperature measurements shed the light on the importance of conformational equilibrium and its influence on association in solution. Moreover, the associates were observed by mass spectrometry. The DFT-based computations for complexes and single bond rotational barriers supports experimental data and helps understanding the properties of multiply hydrogen bonded complexes.

contents Dilution and titration charts S2 Collective data for changes in (CH 2 ) during titrations S8 Correlation charts S9 Inflection point analysis S10 NMR spectra S12 VT 1 H NMR spectra S14 The NOE spectra S18 Geometry of the optimized structures S19 Cartesian coordinates of the optimized structures S26 Opposite effect of substituent on association (additional discussion) S42 Additional discussion (HOMA based and substituent effect) The titration curves behave like a linear function in the range between ca. 0.5 and 0.8 [G]: [H]. For this range the straight line was fitted giving various slope values. The said slopes are dependent from the substituent constant after removing some points. For the R = NMe 2 , Me, Cl, CF 3 and NO 2 set the correlation coefficient is equal to R = 0.94 ( Figure S14). This value shows the tendency in the substituent-driven association in the region of fast conformational changes. The deviations of the remaining three substituents from the trend may be caused by a small amount of water in the samplesalthough we used dried solvents some compounds may be more hygroscopic than others. Figure S14. The correlation of the slope = f (substituent constant) from partial titration data -selected points (left) and the full set of data (right) in titration charts  Since the data of the 1 H NMR titration shown that more than two forms are present in solution making the association non-specific the data were treated mathematically to find if the inflection point of all titration curves is depended from the substituent (the dose-response function was used [1]). The position of the inflection point correlates with substituent constant (Table S1). It is important to note that the correlation between position of the inflection point on the Y-axis ( infl [ppm]) and  values (for linear function  infl =f()) is higher than that for X-axis ( Figure S16. The position of the inflection point on Y-axis for both protons (H1/H7 and H3/H5, Figure S16) is higher for benzoates carrying electron-donating substituent than that for electron acceptors. This is in agreement with the hydrogen bond accepting abilities of anions carrying electron-donating substituents. On the other hand, it is interesting that the position of inflection point on X-axis in titration curves ([G]:[H] infl ) is also higher for electron-donating substituents than that for acceptors (Table S1). This suggests that the structure shown in Figure 4 may be important in the beginning of the titration. Thus, most probably, at low [G]:[H] ratio the anion interacts with a dimer 1e 2 forming bifurcated hydrogen-bonding complex as shown in Figure 4 and when the concentration is higher the dimer dissociate giving the opportunity to form heterocomplex. At the same time the electron donating substituent causes enhanced stabilization of 1e•••anion associate shown in Figure 5 (main text) by bifurcation of the hydrogen bonds. This, in turn, causes shift of the 1e1a equilibrium (or other forms) towards higher concentration of the salt shifting the ([G]:[H] infl ) to higher values. After reaching the critical concentration of the salt the stability of the hydrogen-bonded complexes is driven by substituent. This is manifested by the higher CIS and  infl values for electron donating substituents than that for electron acceptors (see Figure 6 in main text and Table S1). S12 NMR spectra (CDCl 3 , 20°C) 1 H NMR spectrum of 1 13 C NMR spectrum of 1 S13 1 H NMR spectrum of 10  We would expect that NH/NH (H1/H3) NOE signals would be observed if at low temperatures 1a form is present in its multimeric structure (Figure 4) or as associate. Since no strong cross-peak is observed we concluded 1a is not present at lowered temperatures neither in 1 nor in its complex with 5.

S19
For the simplicity of computations the n-butyl group was replaced by methyl. Such structure is labeled as 1'.   Figure 10 in main text) E = -1208.4117724 a.u., imaginary frequency -51.  The above discussion on nonlinearity of association leads to the conclusion known from the other publications that preorganization [2] of organic molecules and their rigidness is crucial in the light of supramolecular chemistry, while flexibility causes problems in predicting properties. However, it is worth mentioning that in biochemical reactions based on enzymes the said flexibility allows effective interactions due to the geometric demands of molecules (also in metal-organic frameworks [2]) and thus it is crucial for reactions responsible for such processes.

Changes in conjugation of 1' upon conformational changes
The electron conjugation in some dibuthyltriuret forms stabilized by intramolecular hydrogen bonding additionally stabilizes these conformations. Such stabilization is called resonance-assisted hydrogen bond [3] and is expressed by strengthening of intramolecular hydrogen bonding that, in turn, influences the overall stability. Here two approaches were used to test geometry and associated energy  Table S2 collects the detailed data.  telling that association is worth the E (1'a) rel to be paid.

Discussion of the substituent effect on association
As it was shown before the substituent effect influences the association of benzoates [5,6]. However, the interaction with benzoates also depends on the structure of counterpart carrying hydrogen bond donors. In the current study the substituent effect is not strong and does not have a highly linear character. S46

Computations
In all calculations the methyl group was used instead of n-Bu. The structure is labeled as 1'. For all forms of 1' and its complexes full geometry optimizations were performed. Moreover we have also run the calculations that helped us to understand the rotamerism in the studied complexes (rotational transition states in 1' and its complex with 5 and 10). Also, the various doubly hydrogen-bonded complexes of 1' were examined.
The rotamerism in 1' and its interaction with 5 Table S3 collects the relative energy of rotamers ( Figure 2 in the main text) of The data in Table S3 are in agreement with experimental results [10] and general observations known as Etter's rules [11] regarding formation of intramolecular S47 hydrogen bonds, i.e. two, the most stable forms are 1'd and 1'e -both stabilized by two intramolecular hydrogen bonds (the sum of E HB form these to are -61.1 and -55.8 kJ/mol, respectively). The relative energy between these forms is small, but to convert 1'd into 1'e it is necessary to pass through structure 1'c -rotations about N3-C4 (1'd1'c) and C2-N3 (1'c1'e). This path (dce) yields with two rotational transition states. Forms 1'd and 1'e are capable to form complexes with benzoate anion by double hydrogen-bonding, while 1'c can form two various hydrogen bonded complexes stabilized by hydrogen bonds and attractive secondary interaction ( Figure   S32). The strongest intramolecular electronic repulsion on one hand and the strongest intermolecular interaction on the other (up to four hydrogen bonds) should be present in associate with 1'a (see Figure 3 in the main text, left structure). If so, the alternate rotameric path should be considered starting form the same, the most stable, 1'd form.
S48 Figure S33. The energetic of rotamerism in 1' The dce path starting from the lowest in energy 1'd is more probable. However, it is worth noting that it must pass through the 1'c form. If 1'c form is probable the form  Figure   S29, side view). In Figure S34 similar calculations are presented but the rotamerism is of "anion-assisted" type. The anion-assisted rotamerism passing through the 1'c-TS-1'a state was omitted due to much lower in energy 1'd-TS-1'c and 1'c-TS-1'e states.

S49
The energy of transition states in associates show that in most cases the transition state energy (versus the most stable 1'd•••5 complex) is higher than the respective transition state energy in uncomplexed 1'. However, when one compares Figure S33 and S34 side-by-side it is easy to note that for 1'a•••5 and 1'c•••5 their relative energy is lower than 1'a and 1'c with respect the most stable form (1'd•••5 and 1'd, respectively). This is observed for complexes that are able to form more than two intermolecular hydrogen bonds suggesting that these rotamers are more probable to exist as associates than in 1' if only the rotational barrier is reached. Moreover, since the repulsive inter-(secondary) or intramolecular (electronic repulsion) interactions exist in every associate the intermolecular interactions in transition states are stronger than that in structures in energy minima. This is caused by twisting groups responsible for repulsion by ca. 90 degrees in the transition state. The subtle balance between these forces is important in such a complicated equilibrium independently from the relatively small size of molecules.
Based on the QTAIM it is possible to calculate the hydrogen bond energy also for weak interactions of CH···X type [12] or relatively long hydrogen bonds. [6] Table   S4 collects the QTAIM derived data for complexes of 1'•••5.  (Figure S34). The said numbers confirm 1 is a flexible molecule with the ease of association, rotamerism and thus formation of multiple supramolecular structures.

Interaction of 1' with 10
The interaction of 1 with 10 showed that two forms coexist in solution. The following computational data with a proposed mechanism leading to a coexistence of two forms support experimental findings. In Figure S35 the energy diagram shows the relative energy of transition states and locally stable form (1'c•••10 (form1)) between more stable forms (in red, Figure 10 in the main text). Table S5 collects