Influence of Environmental Humidity on Organization and Molecular

Article pubs.acs.org/JPCB

Influence of Environmental Humidity on Organization and Molecular Dynamics of Heteromacrocyclic Assemblies Piotr Paluch,† Sławomir Kaźmierski,† Agata Jeziorna,† Justyna Sniechowska,† Kajetan Dabrowa,‡ Jaroslaw J. Panek,*,§ Aneta Jezierska-Mazzarello,§ Janusz Jurczak,*,‡ and Marek J. Potrzebowski*,† †

Polish Academy of Sciences, Centre of Molecular and Macromolecular Studies, Sienkiewicza 112, 90-363 Lodz, Poland Polish Academy of Sciences, Institute of Organic Chemistry, Kasprzaka 50, 01-224 Warsaw, Poland § University of Wroclaw, Faculty of Chemistry, F. Joliot-Curie 14, 50-383 Wroclaw, Poland ‡

S Supporting Information *

ABSTRACT: 1D and 2D NMR study, Car−Parrinello molecular dynamics, as well as classical molecular dynamics were employed to investigate three derivatives of benzodiazacoronands (achiral compounds which are able to form single crystals with a planar chirality) with intention to explain all subtle effects important during their preorganization, the step anticipating formation of crystals. The experimental study was carried out in two solvents: chloroform and DMSO either containing traces of water (commercial samples) or carefully dried over molecular sieves. Both methods revealed that environmental humidity has a dramatic influence on topology of solute−solvent interactions. Damping of the macrocycle dynamics by its diverse types of interactions with water molecules was shown by computational means. In the most spectacular experiment, we have proved that in chloroform-d during the low temperature measurements traces of water dramatically change the spectral pattern, leading to isochronous NMR signals of the AB spin system of benzodiazacoronand. The temperature of isochronous point (TIP) strongly depends on the benzodiazacoronand/water (BW) ratio. This observation opens a pathway to a new strategy based on variable temperature crystallizations and fitting of BW ratio with hope to optimize conditions for formation of chiral crystals.

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INTRODUCTION Cyclic macromolecules are important and interesting systems commonly used as models for basic studies and in applied chemistry for manufacture of daily used products.1,2 Depending on assumed functions, the macrorings with defined molecular structure are constructed. Actually, the collection of different cyclic macrosystems is incredibly rich, and their methods of synthesis and practical applications were reviewed in a number of papers and textbooks.3−5 In recent years, much attention has been paid to chiral macromolecules as promising systems for applications in chiral recognition and asymmetric synthesis. Various classes of chiral concave molecules including cyclic amides, cyclotriveratrylenes, homooxacalix[3]-arenes, calixarenes, resorcinarenes, phthalocyanines, corannulenes, and cavitands were recently reported.6 Most of the given supra compounds possess well-defined stereogenic centers. On the opposite pole of the strategy leading to formation of chiral macrocycles are achiral compounds which become chiral by self-organization in the solid phase.7 Chiral crystals formed from achiral molecules have received a great deal of attention due to their attractive structural properties and prospective applications in chemistry.8 Understanding the details, which govern the process of formation of chiral crystals, chiral induction, and the mechanism of © 2013 American Chemical Society

spontaneous resolution of racemic compounds, is still a matter of debate.9 One of the best known examples of formation of chiral crystals from achiral compounds is nucleation of sodium chlorate reported over a hundred years ago by Kipping and Pope.10 In typical crystallization of NaClO3, equal numbers of L- and D-crystals are obtained. As shown by Kondepudi et al. in the 1990s, under specific crystallization conditions (sample stirring), it is possible to achieve “breaking of chiral symmetry” and crystallization of one of the enantiomers with significant excess or even 100% yield. A similar observation was reported for crystals of 1,1′-binaphthyl.11 Recently, our interest has been focused on the preparation of chiral macrocyclic compounds, which are stable in solution and solid state.12−14 As we revealed, the benzodiazacoronads, which belong to the class of compounds with planar chirality, are promising candidates for such a project. In the course of our studies, we have found that atropoisomers of benzodiazacoronands can exist in solution if two independent, indispensable requirements are met: first, the presence of a large intra-annular group that cannot pass through the macroring plane and thus Received: June 26, 2013 Revised: October 8, 2013 Published: October 29, 2013 14420

dx.doi.org/10.1021/jp406308a | J. Phys. Chem. B 2013, 117, 14420−14431

The Journal of Physical Chemistry B

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papers, we have shown that benzodiazacoronands are very hygroscopic systems and in many cases water molecules are occluded in the crystal lattice even if samples are crystallized from pure organic solvents.13,14 It means that the traces of water trapped in the organic environment may play an important role in the preorganization process, which anticipates the formation of chiral and/or achiral crystals. This observation prompted us to pursue more detailed structural studies of compounds under discussion in order to explain phenomena, which can be important during the process of nucleation.

defines its top and bottom side; second, the presence of a group that differentiates between the left and right side of the macrocycle (Scheme 1). Scheme 1. Reason for Planar Chirality in Macrocyclic Compounds in the Liquid Phase (upper trace); Different Modes of the Molecular Motion Which Can Be Considered for the Samples under Investigation (bottom trace)

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EXPERIMENTAL PROCEDURE Simple 1H, 13C spectra and all 2D experiments were measured on an Avance III 600 MHz Bruker Spectrometer operated at frequencies of 600.13, 150.76, and 60.91 MHz for 1H, 13C, and 15 N, respectively, equipped with 1H, 13C, and 15N TXI Bruker RT probeheads with z-gradient. In the ROESY experiment, the mixing time was set to 250 ms. All 2D heteronuclear experiments were carried out with the pulse field gradient. The assignment of signals was confirmed by sets of 2D experiments (1H−1H COSY, 1H−13C HSQC, 1H−13C HMBC, 1 H−15N HSQC). Full spectral data is available upon request to the authors. Extra dry (ed) solvent was prepared from a commercial sample by drying over freshly activated 3 Å molecular sieves (in the case of CDCl3 preceded by deacidification of dry K2CO3). The water concentration in CDCl3 was determined by coulometry using a 756 KF Coluometr Metroohm system. In pure CDCl3(ed), the water content was lower than 10 ppm, and in the case of CDCl3(tw) with traces of water, the maximal water concentration was 1621 ppm. In the case of a solution of 1, 2, or 3 samples, the water concentration was determined by integration of the water signal. In DMSO, the water content was determined only by integration when the sample concentration was known. The typical sample concentration was found to be 0.05 mol/dm3 or lower.

In the solid phase, lariat-type macrocycles, which do not fulfill the second condition (achiral organic compound), can be obtained in the form of crystals with planar chirality if the lariat group is located in the one defined position. Hence, the local molecular dynamics of the sample during the crystallization can be a critical factor responsible for the final form of crystals. The different modes of the molecular motion which can be considered for samples under investigation are shown as the bottom trace in Scheme 1. The motion labeled as 1 is a flip of the lariat group through the macroring plane, 2 is the flip back of the lariat group, 3 is a rotation around C−C, C−N, or C−O bonds, and 4 is ring puckering. Searching the number of achiral benzodiazacoronands, we have found that only few compounds crystallize in chiral space groups. For instance, samples 1 and 2 crystallize as racemate while sample 3 as enantiomer (Scheme 2). In our previous

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COMPUTATIONAL METHODOLOGY

The structures of 1−3 benzodiazacoronands were optimized at the DFT level using the three-parameter Becke functional, B3LYP,15 and the polarized double-ζ split valence Pople’s basis set, 6-31G(d,p).16 The molecular complexes of the studied compounds with water (obtained from the molecular dynamics trajectory; see further) and DMSO were also optimized at the B3LYP/6-31G(d,p) level, and the final interaction energy was calculated with the B3LYP functional using the 6-311G(d,p) basis set17 and taking into account the basis set superposition error (BSSE) with the a posteriori Boys−Bernardi scheme.18 These static calculations were carried out with the Gaussian 09 suite of programs.19 The optimized structures of the benzodiazacoronands were then used as input data for non-solvated (gas-phase) Car− Parrinello20 molecular dynamics. Each molecule was placed in a 20 Å cubic cell, and the periodic images were removed with the Hockney scheme.21 The electronic structure was described within the DFT framework and the Perdew−Burke−Ernzerhof functional, PBE.22 While the valence Kohn−Sham orbitals were expanded using a plane-wave basis set with 75 Ry kinetic energy cutoff, the core electrons were replaced by norm-conserving Troullier−Martins pseudopotentials.23 The temperature (300 K) was controlled by Nosé−Hoover thermostat chains24−26 coupled to each ionic degree of freedom. Time evolution of

Scheme 2. Structures of Benzodiazacoronands with the Numbering System

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Figure 1. The most diagnostic fragments of spectra 1H (A−D) and 13C (E−H) for sample 1 recorded in extra dry (ed) and with traces of water (tw) solvents.

long, was performed in which the collective variable was constrained to a specific value (ranging from 4 Åslightly larger than the equilibrium value determined from the Car− Parrinello MDto 0 Å) by a harmonic potential. The values of constraint force constants were adapted to provide consistent sampling of the collective variable range. The umbrella sampling results were analyzed with the use of the WHAM 2.0.4 program.33 Car−Parrinello and classical MD trajectories were analyzed with the help of the VMD 1.8.7 program34 and locally written scripts to derive root-mean-square fluctuations, pair distribution functions, and solvation shell structures. The snapshots of the classical MD were also used to prepare models for interaction energy studies mentioned above; while the initial structures of the ligand−water complexes were directly adapted from the MD snapshots, the ligand−DMSO structures were prepared by atom replacementthe DMSO molecule was built on top of the water oxygen atom. Such small models were then used in the DFT structural optimizations and calculations of interaction energies, as described earlier.

Car−Parrinello equations was carried out with a time step of 3 au and a fictitious orbital mass of 400 au. After the initial equilibration phase, the trajectory was collected for 5 ps. This part of the calculations was carried out with the CPMD 3.11.1 package.27 The molecular dynamics with the classical force field was carried out as well for the studied benzoazacoronands both in the gas phase and in the water solution. The GAFF force field28 was used to describe the macrocyclic ligands, while the TIP3P model29 was employed for water molecules. Each macrocycle was placed in a rectangular box filled with the TIP3P water, with at least 12 Å distance between the ligand and the box boundary. The particle mesh Ewald method with a direct summation cutoff of 12 Å was used to calculate the energy of the cell. The initial minimization (1000 steps) was performed to remove artificially short contacts. Then, the molecular dynamics run with a time step of 1 fs was carried out in the following substeps: first, equilibration was performed by gradual heating under constant volume (0 to 100 K, sustained 100 K, 100 to 200 K, sustained 200 K, 200 to 300 K, and sustained 300 Keach of the six phases 50 ps long); next, a second stage of equilibration, 200 ps long, used the 300 K thermostat and 1 atm barostat to bring the system to the standard conditions; finally, the production run was performed for 5.5 ns in the NPT ensemble (T = 300 K, P = 1 atm). The time scale of the production run was chosen to reproduce the changes in solvation shell and torsional dynamics of the macrocycle. The classical molecular dynamics calculations employed the PMEMD code of the AMBER9 suite of programs.30 The flip motion of the lariat group was studied by the umbrella sampling technique31 followed by the weighted histogram analysis method (WHAM)32 to recover the free energy profile. This part of classical force field MD calculations used the equilibrated structures from the production MD run, and employed the same setup (explicit water as solvent). The collective variable was the distance between the geometric center of the lariat phenyl ring and the center of the macrocycle (defined using the heteratoms only). A series of runs, each 3 ns

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RESULTS AND DISCUSSION Influence of Environmental Humidity on NMR Spectral Parameters of Benzodiazacoronands. The challenge for NMR spectroscopy is the analysis of solute− solvent contacts in term of strength and topology of noncovalent interactions. The common types of such interactions are hydrogen bonds (HB), ionic bonds, van der Waals forces, and hydrophobic interactions. Inspection of the structure of benzodiazacoronands shows that this type of compounds possesses both H-donor (N−H groups) and H-acceptor ( O, CO) sites in the macroring (Scheme 2). The lariat groups can serve as H-acceptor (O-benzyl) or H-donor and Hacceptor (N-benzoyl) residues. In the current project, we have analyzed three compounds (see Scheme 2) in two deuterated solvents (dimethylsulfoxide, chloroform) used in extra dry (ed) form and with traces of water (tw). The complete 1H, 13C, and 15 N NMR spectra with signal assignments are included as 14422



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The hydrogen bonding also has an influence on 15N chemical shifts. Figure 3 shows 1H−15N gHSQC correlation for sample 1

Supporting Information. Figure 1 shows the most diagnostic fragments of the spectra for sample 1 recorded in ed and tw solvents: DMSO-d6 and chloroform-d. From inspection of 1H NMR spectra (left column), the significant distinction of the chemical shift of NH protons for both solvents is seen. In DMSO-d6, the NH proton of the lariat group (NHL) is downfield shifted ca. 2.5 ppm compared to the NH of the macroring (NHM) found at δ equal to ca. 7.5 ppm. In chloroform-d for both protons (NHM and NHL), the chemical shifts are comparable and these signals are found at δ equal at region 7.5 ppm. Such differences can be explained in terms of hydrogen bonding. It is well-known that DMSO can act as a HB acceptor. For example, DMSO is thought to disrupt the secondary structure of polypeptides by strong hydrogen bonding.35 In the case of sample 1, DMSO interacts strongly with NHL, which is outside of the sphere of the molecule, and very weakly with HM, which are hidden in the interior sphere of 1. The orientation of DMSO with respect to the molecular shape of 1 in pictorial form is displayed in Figure 2A. The

Figure 3. 1H−15N gHSQC correlation for sample 1 with apparent differences in position of correlation peaks: (a) ed; (b) wet. Ratio 1:water was changed from 1:0.5 (mol:mol) to 1:1.75 (mol:mol). NHM and NHL were marked by * and +, respectively.

recorded in chloroform with different amounts of water. Distinction in the position of correlation peaks is apparent. From analysis of spectra, it is clear that the lariat N−H group acts as a donor and interacts with water molecules located in the outside sphere of the macroring. Further evidence confirming the strong interactions between 1 and water molecules in chloroform-d(tw) was obtained from the analysis of the 1H−1H ROESY spectrum. Figure 4 shows evident correlation peaks (labeled by blue circles) between the macroring, lariat group, and water.

Figure 2. The orientation of solvents with respect to molecule 1: (A) DMSO; (B) H2O.

theoretical calculations at the B3LYP/6-311G(d,p) level (described further) indicate that, indeed, DMSO can form such complexes with an interaction energy comparable to that achieved by water molecules (ca. −9.5 kcal/mol for DMSO, different bonding scenarios for water give −4.5 to −14 kcal/ mol interaction energy). The water molecule has, however, entropic advantages of being smaller, and thus is able to enter the interior sphere, as well as having both HB-donating and HB-accepting capabilities. Chloroform can only act as a donor in HB; hence, its influence on chemical shifts of NH protons is negligible. It is the reason why the values of chemical shifts for both protons are comparable (Figure 1C). The analysis of 1H NMR spectra for 1 recorded in ed and tw solvents provides further spectacular information. In particular, the case of chloroform is interesting. On the basis of NMR data, we assume that with traces of water first the inner sphere of benzodiazacoronad is hydrated. Due to migration of water molecules into the macroring space and formation of NHM···OH2 hydrogen bonds, a significant shift of NHM protons is observed (Figure 1D). Such water alignment in synergic mechanism can be further strengthened by additional HB interaction of water with the carbonyl C7O group (see Figure 2B). The analysis of shifting of 13C chemical shift in the direction of higher values is straightforward evidence (Figure 1H).

Figure 4. 1H−1H ROESY spectrum for sample 1 in CDCl3(tw). Correlation peaks between macroring, lariat group, and water are labeled by blue circles. The concentration of 1 was 39 mM, and that of water 84 mM. T = 298 K.

Variable Temperature (VT) NMR Measurements of Benzodiazacoronands 1, 2, and 3 in the Liquid Phases with Distinct Humidity. The preliminary VT NMR studies for the samples of 1 and 2 in commercial DMSO, which in our notation is called DMSO(tw), were reported elsewhere.36 The AB proton spin system of C14/23 carbons was used as a probe of the dynamic processes. The isochronous double doublet of HA and HB diastereotopic protons to the singlet was considered as spectral evidence of the molecular motion. In the cited paper, it has been concluded for sample 1 that in DMSO this compound is a rigid system and dynamic processes were not observed. 14423



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Figure 5. VT NMR studies for sample 1 in CDCl3(ed) (a and b) and in CDCl3(tw) (c and d). The concentration ratio 1:water was changed from 1:0.2 to 1:1.75. NHM and NHL were marked by * and +, respectively.

concentration of 1 versus water. This observation prompted us to check whether it is possible at constant temperature to establish in chloroform-d a sample 1:water ratio in which the isochronous effect for the AB system will be seen. Figure 6 shows selected parts of 1H NMR spectra for 1 dissolved in chloroform(ed) and recorded at 298 K. The ratio of water to 1 in the starting point (upper trace) estimated by NMR is established to be 0.06. The inspection of the AB doublet pattern and chemical shifts of NH protons with increase of water concentration clearly shows the changes of spectra. In the range of 1:water ratio from 0.69 to 0.96, we observed the isochronous AB system represented by a single line. Further increase of water content in the solvent causes the appearance of a double doublet. The AB doublet under discussion resembles the “NMR hourglass”, and such a picture to the best of our knowledge is reported the first time. Analysis of chemical shift drift for NH protons is an additional source of interesting information. As seen, the drift of NHM protons is significant, while the position of NHL is almost constant. It suggests that during the hydration of sample 1 water penetrates the interior space of macroring, forming hydrate with water bonded as donor to carbonyl group C7O and as acceptor with NHM. Such a picture is supported by analysis of changes of 13C chemical shift shown as the right column in Figure 6. We suppose that water contributes in three hydrogen bonds, two as donors of hydrogen bonding with C7O and C18OC17 and one as acceptors of hydrogen bonding with NHM. It is consistent with observation of NOE (water−NHM, water C21H2) shown in Figure 4 and 1H−15N correlations presented in Figure 3. The understanding of NMR effects on the molecular level which correlate all factors discussed supra is challenging. Trying to build up the concise picture which in our opinion is the best explanation of NMR phenomena for 1, we assumed that the

Our measurements carried out in DMSO(ed) and DMSO(tw) in the temperature range from 293 to 363 K confirmed the previous analysis; however, explanation of the observed effect in the light of our current studies is vague. Intriguing behavior of 1 was observed in chloroform-d measured in the temperature range from 323 to 253 K. Parts a and b of Figure 5 show selected fragments of 1H spectra in ed solvent. The ratio of 1 to water is found to be 1:0.2 (mol:mol). Parts c and d of Figure 5 display fragments of 1H spectra in tw solvent with a 1 to water ratio equal to 1:1.75 (mol:mol). The distinction in spectral pattern, in particular for AB doublets (Figure 5b and d) is dramatic. For the sample in ed chloroform with a decrease of temperature, we observe a decrease of the chemical shift gap for A and B protons (Figure 5b). At 253 K, signals are isochronous. For 1 recorded in tw chloroform with the increase of temperature, we noted a decrease of the difference of chemical shifts between the HA and HB protons, and finally, at 313 K, the isochronous signals at δ1H equal to ca. 4.6 ppm (Figure 5d) were seen. The behavior of 1 in chloroform-d is very uncommon and to the best of our knowledge has never been reported in rgw literature. The low temperature isochronity of diastereotopic protons is not apparent, and an explanation of this phenomenon is not trivial. We obtained interesting information analyzing the change of chemical shifts for the NHM and NHL protons as functions of temperature. It is well-known that δ shifting of protons is a measure of the strength of hydrogen bonding and contacts between donor and acceptor.37 The red asterisks in Figure 5 reflect the change of the NHM protons, while the blue ones shift of the NHL protons. As one can see, in the case of sample 1 in chloroform(tw), differences for NH protons are much bigger. Detailed analysis of the system under investigation has revealed that the NMR temperature of the isochronous point (TIP) for the AB spin system depends on the relative 14424



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cone. Small changes of the torsion angle, related for example with incorporation of water into the internal space of the macroring, can influence the shielding of both protons, causing even reverting of their chemical shifts (see changes for C14 and C17carbons). It is worth stressing that diverse C12−C13−O− C23 (or C10−C9−O−C14) torsion angles for 1 were found in the X-ray structures.12,13,36 Our discussion so far was focused on isolated molecules of 1 which can exist as water inside form (WIF) or water outside form (WOF) with respect to the macroring. On the macroscopic level, we have of course a mixture of both forms and exchange between WIF and WOF. Measured spectra are averaged by fast exchange between WOF and WIF. Assuming equilibrium: WOF + H 2O = WIF

The equilibrium constant is given by

Kf =

[WIF] [WOF][W]

Kf =

[WIF] (Co − [WIF])(Cw − [WIF])

where [WIF] is the equilibrium concentration of WIF, [WOF] is the equilibrium concentration of WOF, [W] is the equilibrium concentration of H2O, Co is the initial concentration of compound determinated by weighting sample and solvent, and Cw is the initial concentration of H 2O determinated by integration of the water signal. Solving the equation for [WIF]: [WIF] = 1 + K f (Co + Cw) −

Figure 6. NMR titration of sample 1 in CDCl3(ed) by wet CDCl3. NHM and NHL were marked by * and +, respectively.

1 + K f 2([Co − Cw)]2 + 2K f (Co + Cw) 2K f

The observed chemical shift δobs is expressed by formula: distinction of chemical shift for protons of CH2 groups (C14/ C23) and other components (a big change of chemical shift is also seen for C11H, C12H, C14/24H, C14, and C17) is due to the ring current of the central phenyl residue (C8−C13). The NMR shielding for the fragment of sample 1 in pictorial form is shown in Figure 7. Depending on the orientation of phenyl with respect to methine group which can be measured by C12−C13−O−C23 (or C10−C9−O−C14) torsion angle, the diastereotopic HA and HB protons can be found in different place of anisotropic

δobs =

(Co − [WIF])δ WOF [WIF]δ WOF + Co Co

where δWOF is the chemical shift of pure WOF and δWIF is the chemical shift of pure WIF. By NMR titration and fitting calculated chemical shifts with experimental data (using home written code in Mathematica 9), we established Kf for 1. At a temperature of 298 K, the value is equal to 85.2 ± 3.1 (for details of analysis of NMR titration data, see the Supporting Information). Kf is temperature dependent. Changes of equilibrium constant Kf as a function of temperature (described by the van’t Hoff equation) explain differences in spectra shown in Figure 5. We observed similar effects for sample 2, although the results are not as spectacular as for compound 1. The traces of water have a significant influence on chemical shifts. Figure 8 shows the diagnostic AB proton spin system of the C14/23 carbons with labeled TIP. Columns a and b represent sample 2 in chloroform-d, dry and wet, respectively. Figure 8c shows 2 in DMSO-d6(ed), while Figure 8d shows spectra in DMSO-d6 with traces of water (tw). From the comparative analysis of the data, it is clear that the traces of water make TIP higher by about 10 K for both solvents when the ratio 2/water changes from 1:1.15 to 1:18. Employing the NMR titration procedure, we established the Kf value for sample 2 in chloroform. Kf is found to be 38.7 ± 3.4.

Figure 7. 3D structure of 1 with marking ring current causing changing of chemical shift. 14425



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Figure 9. VT NMR studies for sample 3 in DMSO-d6(ed) (left column) and in DMSO-d6(tw) (right column).

shorter than that of C3, while in chloroform(ed) ca. 55%. This result suggests that, in addition to the global tumbling of a molecule, the lariat group undergoes the local motion with rotation of the phenyl ring around the C3−C6 axis, labeled in Scheme 1 as case 3. The difference between the dry and wet environment suggests further that in chloroform containing traces of water rotation of the phenyl lariat group is slowed down. Another source of interesting information about molecular dynamics of 1 is an analysis of the correlation times for the aliphatic CH2 groups of the macroring. In chloroform(ed), the correlation times for C14/23 are slightly lower compared to C16/21 and C17/20, while, in chloroform(tw), the opposite trend is observed. A similar molecular motion of 1 was observed in DMSO-d6. It can be shortly concluded that, as in the previous case, the lariat group undergoes rotation about the C3−C6 axis and in DMSO-d6(tw) the rotation is more restricted; the methylene carbons follow the same trend in dry and wet solvent. For sample 2, in both solvents, the central part of the molecule (aromatic ring, carbons C10/12 and C11) is relatively rigid or undergoes molecular motion which is not recognized by the 13C T1 measurement. The rotation of the lariat group is apparent. Moreover, τc values of the macroring methylene groups gradually decrease for carbons more distant from the lariat group. It means that C14/23 is the most rigid, while C18/19 is the most flexible part of the macroring. Hence, we can conclude that the macroring of 2 undergoes puckering (labeled as 1 in Scheme 1) with a small amplitude of motion close to the central phenyl ring (C9−13) and much larger for remote CH2 groups (carbons C18/19). The study of the correlation times for sample 3 confirmed that the lariat group rotates in both solvents and the macroring is relatively rigid. In general, from the 13C T1 measurements in ed and tw solvents for all samples, it can be concluded that water slows down overall tumbling of the molecules, forming solute−solvent assemblies. Theoretical Investigations of Microsolvation of Benzodiazacoronands. In a theoretical approach, the determination of local solvation spheres is a challenging task for investigations of behavior of bulk liquids38 as well as atmospheric aerosols.39 The traces of water present in aprotic

Figure 8. VT NMR studies of the diagnostic AB proton spin system of C14/23 for sample 2 in (a) CDCl3(ed), (b) CDCl3(tw), (c) DMSOd6(ed), and (d) DMSO-d6(tw).

Finally, we investigated sample 3 which in the lariat group possesses only an acceptor of hydrogen bonding. The oxygen of the O-benzyl moiety interacts with the HM protons, forming an intramolecular HB. Due to this contact, the structure of sample 3 is more compact compared to 1 and 2 and resembles the partially closed shell. We predict that for such a structure penetration of the interior space of the macroring by water is difficult or impossible. VT 1H NMR measurements have confirmed this assumption. The diagnostic HM protons are insensitive to changes of humidity of the environment and change of temperature. This conclusion is valid for both solvents (see Figure 9). It is worth noting that diastereotopic geminal protons of the C7 methylene group are isochronous. It can be due to the fast (in the NMR time scale) rotation of the lariat group around the O−C and/or C−C bond. Molecular Dynamics in the Liquid Phase-NMR Study. The relaxation NMR data were employed to analysis of reorientation of the entire molecules, or of their molecular segments. The overall and segmental mobility of host−guest complexes was studied by the measurement of their 13C spin− lattice relaxation time (T1). Details describing results and methodology are attached as Supporting Information. The analysis of data proves that the values of correlation times τc very well reflect the distinct molecular motion of individual segments of 1. For instance, the correlation times of C1/C5 and C2/C4 are smaller compared to other carbon centers. The comparison of their τc with τc of C3, which belongs to the same phenyl ring, is especially interesting. In chloroform(tw), the τc of C1/C5 and C2/C4 are ca. 30% 14426



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bond(s). If, however, a water molecule enters this space, the resulting new HBs are as strong as those for 1 or 2. Therefore, the relative hydrophobicity of the interior of 3 is of partially entropic nature: a water molecule must first destroy the preexisting HB network in the macrocycle in order to form even stronger interactions, and since there are two intramolecular hydrogen bonds to be broken in 3, the associated energetic cost and increase in flexibility (increase of entropy) are larger than in 1 or 2, requiring only one bond to be broken. This makes the interior cage of 3 seemingly more hydrophobic than the cages of 1 or 2. On the other hand, 1 and 2 prefer binding of water in the macrocycle interior. Water acting as a multiple HB donor/ acceptor at the same time disrupts one of the NHM···OL bonds, but in this case, there is enough room for the other bond to be intact. DMSO interacts with 3 at a price of destroying the NHM···OL bonds; therefore, this interaction is not preferred (note that the seemingly strong interaction of 9.43 kcal/mol requires first disruption of the two intramolecular NHM···OL HBs, energies of which are not visible in the tablethis is why the DMSO interaction energies with NHM are practically the same for 1, 2, and 3). On the other hand, water or DMSO can bind to NHL of 1 and 2 with comparable energies. Note that the DMSO−NHL interaction seems weaker by ca. 1 kcal/mol than DMSO−NHM, but this does not include entropy effects and intramolecular HBs which must be overcome to form the DMSO−NHM bond. The outcome would be the preference of DMSO for the NHL moiety. Gas-phase non-solvated Car−Parrinello MD simulations of 1−3 gave us insight into the intensity of atomic motions, represented by root-mean-square fluctuations (approximately: mean amplitudes of motion) around the equilibrium structure. At the relatively short time scale of CPMD, this methodology filters out low-frequency, global motions of the molecule, and local variations in the dynamics are more visible. The results are summarized in Table 2. The computational data correspond to

solvents act in an intermediate way: the amount of water is not large enough to provide consistent hydration, but the presence of solvent molecules slows down molecular motions (including diffusion of water), thus making this situation different from the gas phase humidity. Therefore, in order to describe the studied systems, we adopted a many-step scheme of calculations. Static DFT calculations of ligand−water and ligand−DMSO interaction energies differentiate between various binding sites of the macrocycle. The Car−Parrinello molecular dynamics (CPMD) provides information on atomic motions on a short time scale, and validates the results of the classical force field molecular dynamics (MD). The classical MD operates in a nanosecond regime, enabling us to record ring puckering, the lariat group reorientation, and solvation shell change events. The non-solvated structures of the ligands differ with respect to the intramolecular hydrogen bond network. While for 1 and 2 there is a single bond between the lariat group carbonyl oxygen and one of the macrocycle amide groups (NHM···OL), 3 has two such NHM···OL bonds, and the lariat group lies in a symmetry plane (see the Supporting Information, p S21). The interaction energies for different binding modes of the ligand−water or ligand−DMSO complexes are listed in Table 1. The structures were generated from the classical MD runs and provide representative ensemble of possible hydration modes of the ligands. Table 1. Interaction Energies (B3LYP/6-311G(d,p), BSSECorrected, in kcal/mol) for Ligand−H2O/DMSO Complexesa hydrogen bonds H2O to NHM, OL; NHM···OL H2O to NHM, OL, OM; NHM···OL H2O H2O H2O H2O H2O

to to to to to

NHM, OL, OM NHM, OM; NHM···OL C15/22O; NHM···OL OM; NHM···OL C15O

H2O to NHL DMSO to NHL DMSO to NHM

1

2

−10.45 to −10.62 −11.30 to −13.98 −11.75 −8.91

−10.19 to −10.71 −11.47 to −14.09 −11.62 −8.68

−4.76 to −6.08 −9.28 −8.43 −9.21

−4.61 to −6.12 −9.42 −8.40 −9.73

3

−12.23

Table 2. Root Mean Square Fluctuations (Å) of Selected Carbon Atomsa

−8.89 −8.16 −4.59 to −6.24

−9.43

a

Stronger interaction = more negative energy. Intramolecular hydrogen bonds, if any, are shown after the semicolon sign. Subscript indexes M and L correspond, respectively, to the atoms from the macrocycle ring and the lariat group; see Scheme 2 for the atom naming convention. For detailed structural data and drawings, see the Supporting Information file. a

The data of Table 1 agree well with the NMR measurements in ed and tw solvents. Specifically, the preference of water molecules toward the NHM protons and the C7−OL carbonyl group is visible, in agreement with the observed significant drift of the NHM protons and relatively stable location of the NHL signals (Figure 6). Analyzing the table further, one must remember that the interaction energies reflect only the ligand− water interactions, and energy of any intramolecular HB in the ligand is not visible. Anticipating the MD results, we can say that 3 has a much more compact interior space and the water molecule rarely occupies it; the most frequent binding mode is a solitary contact between a water molecule and the macrocycle. The interior is guarded by the NHM···OL hydrogen

carbon atom no.

2

3

1/5 2/4 3 6 10/12 11 14/23 16/21 17/20 18/19

0.371 0.452 0.421 0.221 0.240 0.256 0.289 0.304 0.318 0.474

0.496 0.602 0.598 0.325 0.328 0.376 0.304 0.374 0.314 0.293

Results from the CPMD simulations.

the NMR results in the following way: shorter correlation times are related to faster motions. The table indicates a larger mobility of the lariat group in 3, which will be shown also later. The macroring is more rigid than the lariat group, and the presence of the phenyl group in 3 additionally stiffens its vicinity (C17/20, C18/19) with respect to 2. Before proceeding to the classical MD results, it is necessary to address the rationale for the simulation protocol: we use a fully hydrated model (i.e., water box) instead of taking into account the presence of the organic solvent. Our initial studies of the mixed models have shown that the water molecule 14427



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Figure 10. NM−NM and OL−OM distance along the MD trajectory for 1 (top left) and 3 (top right). Dihedral angles along the MD trajectory describing the lariat rotation 3 (bottom left for 1, around the C8−NL bond; bottom right for 3, around the OL−C7 bond).

Taking all these factors into account, we prefer to use the fully hydrated model for classical MD, which provides better statistical sampling of different hydrogen bonding scenarios, at the expense of only semiquantitative accuracy of the calculated flip back motion barrier. Classical molecular dynamics, in the fully hydrated model, served us to estimate the ligand flexibility and solvation shells. One of the possible measures of ligand compactness is the size of the interior cavity of the macrocycle. To approximate this size, we plotted graphs of the NM−NM and OL−OM distance along the MD trajectory (Figure 10, top). The diameter measured across the NM−NM gap behaves in a similar fashion for 1 and 3. On the other hand, the result for the OL−OM parameter (apparently more compact cavity for 1) seems surprising, but one should take into account that a water molecule is frequently present in the middle of the cavity in 1 and 2 (which will also be shown later), so that the OL atom closes the cavity from above. This makes it closer to the opposite edge of the macrocycle. When the water molecule escapes (the WIF → WOF transition), the OL is free and a large increase in the oxygen−oxygen distance is visible. For 3, the lariat oxygen atom is dynamically blocking and releasing the entrance to the cavity. The time scale of these processes is consistent with the NMR data: while for 1 there are long regions of relatively stable position of the OL (e.g., the first 2.5 ns followed by conformational change lasting 1 ns), the dynamics of the lariat group in 3 is more chaotic and faster, more resembling free rotation. This effect, in turn, is enhanced by the fact that lariat rotation is hampered in 1 and 2 by the presence of amide bonds. Such restriction is not present in 3, and this is best seen in Figure 10, bottom row, which shows selected dihedral angles. For 1, the most varying dihedral angle

placed close to the ligand tended to diffuse away into the bulk. The most important tasks for the classical MD were analysis of solvation and extraction of diverse hydrogen-bonded structures (further used in static DFT calculations, see Table 1 and discussion above). For these tasks, the use of mixed water− organic systems could introduce bias due to insufficient sampling of possible bonding scenarios. We therefore considered the impact of the use of a fully hydrated model on the dynamics of 1−3. The first factor is the viscosity of the solvent, which macroscopically represents the impact of the solvent on molecular reorientations. Close to the room temperatures, the viscosities of the used solvents are comparable: ca. 0.5 mPa·s for chloroform, 0.9 mPa·s for water, and 2.0 mPa·s for DMSO. On the basis of these values, we expect that the dynamics of 1−3 will be slower in water than in CHCl3 but the qualitative agreement will be retained, and especially the ratios of the molecular motion velocities will remain similar (i.e., the ratios of values in Table 2 are properly reproduced). However, another factor is the presence of hydrogen bonds which can exist between the solvent (water, DMSO) and ligand, as well as between the solvent molecules (water only). This factor will also hamper the dynamics of the coronand, and will additionally increase energy barriers for intramolecular reorganization of coronands, because the intrasolvent and solvent−ligand hydrogen bonds must be reorganized during a reorientation motion (e.g., any of the motions depicted in Scheme 1). However, this effect has the most impact on the barrier height calculated for the flip back motion; the results of the barrier calculations indicate that there is a distinct qualitative difference in the behavior of 1 and 2 versus 3. This would also be the case even in the simulated organic solvent, although the barrier height would be lower. 14428



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Figure 11. Radial distribution functions for atomic pairs between the indicated atom and solvent water oxygen atoms. Red, data for 2; green, 3.

is connected with rotation around the C8−NL bond, which is formally a single bond. Its position between the amide bond and phenyl ring, as well as friction from surrounding water molecules, results in restriction of the rotation to libration between 40 and 150°. The slowing down of this rotation of the lariat phenyl group was found in 1 experimentally in the presence of humidity. For 3, the most varying angle describes rotation around the OL−C7 bond, and while it is usually close to 180° (corresponding to the compact form of 3, in which the lariat group closes the interior space of the macrocycle), there are events in which the lariat group rotates around this bond. This rotation is consistent with the distance graphs described above. An intriguing question is how these differences in the molecular dynamics of benzodiazacoronands influence the solvation shell around the ligands. The statistical nature of the MD simulations allows calculation of radial distribution functions (RDFs) between pairs of selected atoms of the ligand and oxygen atoms of the solvent (water). These functions are presented in Figure 11. Surprisingly, neither the macrocycle nitrogen atoms NM nor the lariat nitrogen NL (in 2) seem to form stable solvation shells, distinguishable by sharp peaks in the RDFs. On the other hand, the oxygen atoms of the C15/22 carbonyl form well-defined contacts with water (the most frequent O···O distance of 2.85 Å). These contacts can be assigned to be primarily responsible for the change of the behavior between the ed and tw solvents in the experiments. The lariat oxygen OL is also able to form a weaker, less prominent close solvation shell, but only for 2no similar shell is present in 3. This fact emphasizes the more flexible interior space of 1 and 2, able to accommodate water molecules resulting in the WIF form of the system, against the closed, less penetrable interior of 3, where the OL readily takes part in the intramolecular hydrogen bonding with NHM. Further, the dynamic nature of the microsolvation shell was investigated by

counting occurrences of the WIF and WOF forms for the classical MD simulation of 1. The computationally found WIF:WOF ratio of 93:7 is in qualitative agreement with the equilibrium constant estimations on the basis of average NMR shifts of δWIF and δWOF. The corresponding ratio for 3 is 21:79, which shows how much the inner space of 3 is restricted with respect to 1. The restriction leads to the domination of the WOF form. These values were obtained from the MD simulations in water; this allowed us to avoid poor statistical sampling due to the small number of simulated water molecules, which could happen if we were to simulate a system with only traces of water. The final part of the computational investigations consisted of the description of the flip back motion of the lariat group. The simulations were carried out in water as a solvent. Despite our efforts, such simulations for 3 either did not converge or converged to energy barriers above 40 kcal/mol, which indicates rigidity of the structure. On the other hand, somewhat unexpectedly, 1 and 2 gave results similar to each other, despite the fact that 1 has an additional aromatic function which stiffens the macrocycle. We expect the presented simulation in water to yield a larger barrier height than the experimental value in organic solvent, because the flip back motion is associated with local disruption of hydrogen bonds (also within the solvent structure). However, the qualitative difference between the behavior of 1 or 2 versus 3 (a nonconverged simulation) is an indication of a more fundamental issue with the flip back motion of 3, resulting from the increased rigidity of its structure. The results of the classical MD umbrella sampling technique coupled with WHAM analysis are presented in Figure 12 for the coronand 2. The equilibrium structure is on the very right, at the distance between lariat phenyl and macrocycle center equal to 3.9 Å. The energy barrier of the process, 8.7 kcal/mol, is large enough to prevent spontaneous inversion in the standard classical MD 14429



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molecule into the ring must destroy the pre-existing hydrogen bonding network). The computationally derived WIF:WOF ratios underline the fundamental difference between 1 and 3. The role of trace water molecules was highlighted computationally by changes in the motion amplitudes and evolution of interatomic distances when the water molecule is present in the interior cavity. The combined protocols of CPMD and classical MD were found helpful in supporting the experimental findings.

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ASSOCIATED CONTENT

S Supporting Information *

The complete 1H, 13C, and 15N NMR spectra of 1−3 with signals assignment, the methodology, and results of 13C spin− lattice relaxation time (T1) measurements, details on the NMR titration procedure, additional drawings and coordinates of structures of isolated 1−3 and solvated complexes used in interaction energy calculations, and complete refs 19 and 30. This material is available free of charge via the Internet at http://pubs.acs.org.

Figure 12. Free energy profile for the flip motion of the lariat group in 2results of the umbrella sampling classical MD simulation. Reaction coordinatedistance between centers of mass of the lariat phenyl ring and the macrocycle.

simulation on a time scale of several nanoseconds. Another factor is the entropic disadvantage of this process, since, in order to occur, it requires a precise positioning of the lariat group and expulsion of the water molecule from the inside of the interior cavity (an event unfavorable for 1, as indicated by the statistical study of the WIF:WOF ratios).

■

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Phone: (+48)713757246. *E-mail: [email protected]. Phone: (+48)22-3432330. *E-mail: [email protected]. Phone: (+48)42-6803240.

■

CONCLUSIONS The major goal of this project is understanding and explaining all details which on the preorganization level are important in controlling the crystallization process of heterorganic macrocycles. It is in particular important for systems which can be involved in the formation of host−guest non-covalent interactions. In the case of benzodiazacoronands, which are the object of this study, the crystallization is very capricious and unpredictable, especially if we want to obtain chiral crystals. In the complementary approach, which joins NMR studies and theoretical calculations, we explicitly showed how small changes of the humidity of solvents dramatically change the properties of matter. Summing up shortly the important points of this work, first we have established the influence of humidity environment on the nature of host−guest contacts in the liquid organic phase. Employing the 1D and 2D NMR experiments as well as theoretical approaches, we defined the topology of the water− benzodiazacoronand assembly. The measurements of the relaxation time have proved the complex motion of samples including overall tumbling, lariat group rotation, and small amplitude puckering. The CPMD and classical MD simulations are in agreement with these measurements. It has to be stressed that NMR spectroscopy does not offer the tool which can aid in analyzing the flip back motion in terms of scale and geometry. It was done by theoretical methods. The relatively high free energy barrier of 8.7 kcal/mol for the flip back motion of the lariat group in 2 together with entropic hindrance show that the process is outside the time scale of unconstrained molecular dynamics. Moreover, 3 is reproduced as having much higher barriers, which helps in chiral discrimination in this compound. Umbrella sampling provides results which should be considered here as qualitative or semiquantitative, but proving discrimination between the dynamics of the lariat group in 1 and 2 versus 3. Theoretically investigated interactions between the macrocycle and trace water or DMSO are of similar energy, but they differ by entropic contributions (entrance of the water

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the Polish National Center of Sciences (NCN) for financial support, Grant No. 2011/03/N/ ST4/01721. In addition, A.J.-M. and J.J.P. gratefully acknowledge the Wrocław Center for Networking and Supercomputing (WCSS) and Academic Computer Center (TASK) in Gdańsk for providing computer time and facilities.

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REFERENCES

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