Structure, Conformation, and Dynamics of P,N-Containing

Feb 2, 2010 - Sciences, ArbuzoV Str. 8, Kazan, 420088, Russian Federation, and ...... (10) Gibson, W. H.; Wang, H.; Slebodnick, C.; Merola, J.; Kassel...
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Structure, Conformation, and Dynamics of P,N-Containing Cyclophanes in Solution Shamil K. Latypov,*,† Artem V. Kozlov,† Evamarie Hey-Hawkins,‡ Anna S. Balueva,† Andrey A. Karasik,† and Oleg G. Sinyashin† A. E. ArbuzoV Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences, ArbuzoV Str. 8, Kazan, 420088, Russian Federation, and Institut fu¨r Anorganische Chemie der UniVersita¨t Leipzig, Johannisallee 29, D-04103 Leipzig, Germany ReceiVed: August 20, 2009; ReVised Manuscript ReceiVed: December 15, 2009

3D structures in solution of highly symmetrical N,P-containing macrocycles were established by a variety of 2D NMR correlation techniques. It was shown that a number of magnetically equivalent fragments in such symmetrical systems can be estimated by NMR diffusion measurement. The title compounds adopt a helical conformation of the macrocycles in solution. The extent of twisting and the size of the intramolecular cavity are determined by steric hindrance of the aromatic substituents on the exocyclic phosphorus atoms with phenylene and dimethylmethylene groups forming the macrocycle. In solution these macrocycles host aromatic guests inside the cavity. Introduction One of the effective ways in the design of structures with new properties is to preorganize different “active” groups by either covalent or noncovalent bonding.1–4 To this end the systems assembled into macrocycles are of particular interest because in this way it is much easier to confine the “active” species within the well-defined architectures.5–11 Therefore, there is an explosion of interest in the design of macrocyclic hosts for specific guests.12–20 From this point heterocyclophanes containing a number of P,N-heterocycles and aromatic groups are very promising.21–24 First of all, the π-electron system of such heterocyclophanes can interact with aromatic guests. Second, the presence of donor heteroatoms, especially three-coordinate phosphorus, provides a binding site for transition metals as guests.21 With further introduction of various functional moieties on the building blocks, a wealth of P-containing cyclophanes can be potentially employed as precursors of selective sensors,25 systems, which are able to create new types of molecular reactors,26 ligands for transition metal catalysts for electrochemical oxidation and production of hydrogen in fuel cell,27 and used for other applications. This has stimulated studies in the design of macrocyclic tetrakis-phosphines via effective self-assembly processes.28,29 For the rational design of heterocyclophane systems one needs to control the 3D structure of the molecules in solution and to know how it depends on internal/external factors to fine-tune the structure, because potentially useful properties of macrocyclic molecules (for example, molecular recognition, catalytic selectivity, etc.) apparently depend on their spatial structure.30 However, to date there are no reports devoted to conformational analysis of P,N-containing heterocyclophanes in solution. Furthermore, there is an intrinsic obstacle in determining the structure of such highly symmetrical heterocyclophanes in solution by NMR spectroscopy due to magnetic equivalence of its fragments independent of the number of equivalent units. * To whom correspondence should be addressed. Tel.: +7 843 2727484. Fax: +7 843 2732253. E-mail: [email protected]. † Russian Academy of Sciences. ‡ Universita¨t Leipzig.

Figure 1. Structures of investigated compounds with atom numbering scheme.

Therefore, we paid special attention to resolving this problem in frames of the NMR method. We now report an investigation of the conformational structure and dynamics of P,N-containing macrocycles (Figure 1) by NMR techniques. In addition, the factors that have impact on the 3D structure of the macrocycle are also discussed. Finally, the ability of the macrocycles to host large guest molecules in solution is considered. Materials and Methods Synthesis. 13,17,73,77-Tetrakis(2′,4′,6′-triisopropylphenyl)3,3,5,5,9,9,11,11-octamethyl-1,7(1,5)-bis(1,5-diaza-3,7-diphosphacyclooctana)-2,4,6,8,10,12(1,4)-hexabenzenacyclododecaphane (1), 13,17,73,77-Tetrakis(mesityl)-3,3,5,5,9,9,11,11octamethyl-1,7(1,5)-bis(1,5-diaza-3,7-diphosphacyclooctana)2,4,6,8,10,12(1,4)-hexabenzenacyclododecaphane (2)29 and 2,4,6triisopropylphenylphosphine (4)31 were prepared according to procedures reported previously. 1,4-Bis[R-(4′-aminophenyl)isopropyl]benzene (3) was purchased from TCI Europe NV. NMR Spectroscopy. All NMR experiments were performed with a Bruker AVANCE-600 spectrometer (14.1 T) equipped with a 5 mm diameter gradient inverse broad-band probehead and a pulsed gradient unit capable of producing magnetic field pulse gradients in the z-direction of 53.5 G · cm-1. Frequencies are 600.13 MHz in 1H NMR, 242.94 MHz in31P NMR, 150.90 MHz in 13C NMR, and 60.81 MHz in 15N NMR experiments.

10.1021/jp908052f  2010 American Chemical Society Published on Web 02/02/2010

P,N-Containing Cyclophanes Samples (15 mM/L) were prepared by dissolving in 0.6 mL of the corresponding solvent (CDCl3, 99.5% D; C6D6, 99.5% D; toluene-d8, 99.5% D (Deiton, Russia)) in inert atmosphere (Ar) and were placed in standard NMR tubes (Norell, USA). Chemical shifts are reported in the δ (ppm) scale relative to the 1H and 13C signals of tetramethylsilane (TMS) (0.00 ppm). 15 N and 31P chemical shifts were referenced to the 15N signal of CH3CN (235.50 ppm) and 31P signal of 85% H3PO4 (0.00 ppm), respectively. DNMR experiments were carried out using a Bruker variable temperature unit BVT3000 (with BTO2000, accuracy: (0.1 °C, calibrated using a methanol reference). The samples were allowed to equilibrate for 15 min at each temperature. Line shape analysis of signals broadened by chemical exchange was carried out by a DNMR module of Bruker TopSpin 2.1 software package. Activation parameters were calculated according to the Eyring equation.32 1 3 ,1 7 ,7 3 ,7 7 -Tetrakis(2′,4′,6′-triisopropylphenyl)3,3,5,5,9,9,11,11-octamethyl-1,7(1,5)-bis(1,5-diaza-3,7-diphosphacyclooctana)-2,4,6,8,10,12(1,4)-hexabenzenacyclododecaphane (1). 1H NMR (CDCl3): δ 0.99 (d, 3JHH ) 6.7 Hz, 6H, C2CH(CH3)2), 1.28 (d, 3JHH ) 6.9 Hz, 6H, C4CH(CH3)2), 1.35 (d, 3JHH ) 6.4 Hz, 6H, C6CH(CH3)2), 1.55 (s, 6H, C11(CH3)2), 2.89 (m, 2H, C6+4CHMe2), 4.15 (m, 1H, C2CHMe2), 4.33 (d, 2 JHH ) 15.3 Hz, 2H, P-CH2ax-N), 4.44 (d, 2JHH ) 15.3 Hz, 2H, P-CH2eq-N), 6.27 (d, 3JHH ) 8.7 Hz, 2H, C8H), 6.91 (d, 3 JHH ) 8.7 Hz, 2H, C9H), 7.01 (s, 1Η, C5Η), 7.03 (s, 1Η, C3Η), 7.12 (s, 2Η, C13Η) (for numbering see Figure 1). 1H NMR (C6D6): δ 1.24 (d, 3JHH ) 6.9 Hz, 6H, C4CH(CH3)2), 1.30 (d, 3 JHH ) 6.3 Hz, 6H, C6CH(CH3)2), 1.36 (d, 3JHH ) 6.1 Hz, 6H, C2CH(CH3)2), 1.66 (s, 6H, C11(CH3)2), 2.80 (m, 1H, C4CHMe2), 2.99 (m, 1H, C6CHMe2), 4.48 (d, 2JHH ) 15.1 Hz, 2H, P-CH2ax-N), 4.67 (d, 2JHH ) 15.1 Hz, 2H, P-CH2eq-N), 4.72 (m, 1H, C2CHMe2), 6.44 (d, 3JHH ) 8.6 Hz, 2H, C8H), 6.65 (s, 2Η, C13Η), 6.99 (d, 3JHH ) 8.6 Hz, 2H, C9H), 7.15 (C5Η overlapped with benzene), 7.31 (s, 1Η, C3Η). 1H NMR (toluened8): δ 1.24 (d, 3JHH ) 7.0 Hz, 6H, C4CH(CH3)2), 1.30 (d, 3JHH ) 6.8 Hz, 6H, C6CH(CH3)2), 1.31 (br, 6H, C2CH(CH3)2 overlapped with C6CH(CH3)2), 1.66 (s, 6H, C11(CH3)2), 2.79 (m, 3JHH ) 6.9 Hz, 1H, C4CHMe2), 3.03 (m, 3JHH ) 6.8 Hz, 1H, C6CHMe2), 4.51 (d, 2JHH ) 15.5 Hz, 2H, P-CH2ax-N), 4.62 (dd, 2JHH ) 15.5 Hz,2JPH ) 5.4 Hz, 2H, P-CH2eq-N), 4.69 (m, 3JHH ) 6.8 Hz, 1H, C2CHMe2), 6.39 (d, 3JHH ) 8.6 Hz, 2H, C8H), 6.59 (s, 2Η, C13Η), 6.96 (d, 3JHH ) 8.6 Hz, 2H, C9H overlapped with toluene), 7.10 (C5Η overlapped with toluene), 7.26 (br, 1Η, C3Η). 13C{1H} NMR (CDCl3): δC 23.80 (s, C4CH(CH3)2), 24.91 (s, C2CH(CH3)2), 25.94 (s, C6CH(CH3)2), 30.98 (s, C11(CH3)2), 31.50 (d, 3JPC ) 45.0 Hz, C2CHMe2), 34.16 (s, C4CHMe2), 34.26 (s, C6CHMe2), 41.86 (s, C11(CH3)2), 57.99 (d, 1JPC ) 27.3 Hz, P-CH2-N), 113.20 (s, C8), 122.37 (s, C3), 122.45 (s, C5), 126.27 (s, C13), 127.21 (s, C9), 130.51 (d, 1JPC ) 26.8 Hz, C1), 139.62 (s, C10), 143.35 (s, C7), 148.17 (s, C12), 150.22 (s, C4), 153.45 (s, C6), 157.27 (d, 2JPC ) 34.9 Hz, C2). 31 P{1H} NMR (CDCl3): δP -45.49 (s); (C6D6): δP -46.94 (s). 15 N NMR (CDCl3): δN 65.68 (s); (C6D6): δN 64.65 (s). 13,17,73,77-Tetrakis(mesityl)-3,3,5,5,9,9,11,11-octamethyl1,7(1,5)-bis(1,5-diaza-3,7-diphosphacyclooctana)2,4,6,8,10,12(1,4)-hexabenzenacyclododecaphane (2). 1H NMR (CDCl3): δ 1.58 (s, 6H, C11(CH3)2), 2.16 (s, 3H, C4CH3), 2.42 (s, 6H, C2CH3, C6CH3), 4.44 (d, 2JHH ) 15.2 Hz, 2H, P-CH2A-N), 4.49 (d, 2JHH ) 15.2 Hz, 2H, P-CH2B-N), 6.31 (d, 3JHH ) 8.6 Hz, 2H, C8H), 6.73 (s, 2Η, C5Η, C3Η), 6.96 (d, 3 JHH ) 8.6 Hz, 2H, C9H), 7.22 (s, 2Η, C13Η). 1H NMR (C6D6): δ 1.63 (s, 6H, C11(CH3)2), 2.10 (s, 3H, C4CH3), 2.18-2.69 (br

J. Phys. Chem. A, Vol. 114, No. 7, 2010 2589 m, 6H, C2CH3, C6CH3), 4.10 (d, 2JHH ) 15.1 Hz, 2H, P-CH2ax-N), 4.49 (d, 2JHH ) 15.1 Hz, 2H, P-CH2eq-N), 6.41 (d, 3JHH ) 8.0 Hz, 2H, C8H), 6.67 (s, 2Η, C13Η), 6.84 (s, 2Η, C5Η, C3Η), 7.00 (d, 3JHH ) 8.0 Hz, 2H, C9H). 1H NMR (toluene-d8): δ 1.60 (s, 6H, C11(CH3)2), 2.16 (s, 3H, C4CH3), 2.19-2.66 (br m, 6H, C2CH3, C6CH3), 4.15 (d, 2JHH ) 14.8 Hz, 2H, P-CH2ax-N), 4.43 (d, 2JHH ) 14.8 Hz, 2H, P-CH2eq-N), 6.29 (d, 3JHH ) 8.5 Hz, 2H, C8H), 6.61 (s, 2Η, C13Η), 6.80 (s, 2Η, C5Η, C3Η), 6.93 (d, 3JHH ) 8.5 Hz, 2H, C9H). 13C{1H} NMR (CDCl3): δC 20.98 (s, C4CH3), 23.91 (br, C2CH3, C6CH3), 31.43 (s, C11(CH3)2), 41.94 (s, C11(CH3)2), 56.40 (d, 1JPC ) 23.9 Hz, P-CH2-N), 112.73 (s, C8), 126.60 (s, C13), 127.43 (s, C9), 129.46 (s, C3/5), 129.60 (s, C5/3), 130.90 (d, 1JPC ) 31.1 Hz, C1), 139.23 (s, C4), 139.44 (s, C10), 143.53 (s, C7), 147.32 (s, C12). 31P{1H} NMR (CDCl3): δp -42.85 (s). 15N NMR (CDCl3): δN 61.65 (s). Calculations. Molecular mechanics calculations employing the new implementation of Norman L. Allinger’s MM2 force field33,34 were performed with CS Chem3D Ultra 6.0 (CambridgeSoft Corp http://www.camsoft.com.). Shielding effect calculations were carried out using the Shield program35 based on the semiclassical model.36,37 No corrections for local anisotropic contributions were implemented. Calculations were performed with a π-current loop separation of 1.39 Å. The ab initio quantum chemical calculations were performed using Gaussian 98.38 Chemical shifts were determined by the GIAO method39 within the DFT framework using a hybrid exchange-correlation functional, B3LYP, at the 6-31G(d) level if not commented otherwise. All data were referred to TMS (0.00 ppm) for 1H and 13C chemical shifts calculated in the same conditions. Potential energy surfaces and the energy of transition states (activation barrier) were obtained using a relaxed potentialenergy scan for rotation around some bonds with 10° steps at the HF/6-31G level of theory. Results and Discussion Complete structure determination of 1 and 2 was accomplished by a variety of 1D and 2D NMR experiments (COSY, HSQC, 1H-13C/1H-15N/1H-31P HMBC).32,40 2D DOSY41,42 and 1D DPFGNOE43 techniques were used to measure self-diffusion coefficients and NOE’s, respectively. Related 1D and 2D NMR spectra are given in the Supporting Information. Chemical Structure Elucidation. The structure determination of the more complex compound 1 will be discussed in details. For compound 2 bearing exocyclic Mes instead of Tipp groups at the P atoms the analysis was carried out in a similar way if not mentioned otherwise. The elementary subunit of the macrocycle (Figure 2a) can be easily deduced from the internuclear connectivities due to scalar spin-spin couplings (details in Supporting Information). In addition, taking into account nitrogen and phosphorus valences and the multiplicity of phosphorus signals due to JHP, an additional symmetrical fragment can be also restored (Figure 2b). In general, due to a high symmetry of this type of heterocyclophanes the NMR spectra (1H, 13C and 31P) can well correspond to a variety of symmetrical structures obtained by replication of the elementary subunit (Figure 2c). Therefore, additional information about molecular weight (or volume) is necessary to establish the overall structure of such macrocycles. One could invoke mass spectrometry to get the missing information. However, the mass spectra (in particular for

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Figure 2. Structure of subunit and possible hypothetical structures of macrocycle 1.

TABLE 1: Correlation of SDC versus SEV (C ) 1 mM) compound diamine 3

SDC × 10-10, m2/c 10.25 (0.05 a

SEV, Å

SEV,a Å3

M, amu

330

344

3

M, amu no. of subunits

compound 1 2 a

SDC, × 10-10, m2/c 5.87 ( 0.03 6.50 ( 0.07

2

4

6

2

4

6

Vexp, Å3

930 690

1900 1350

2940 2160

864 696

1728 1392

2592 2088

1757 ( 53 1294 ( 61

Mexp, amu 1832 ( 55 1349 ( 65

For low energy conformation.

compounds of large molecular mass) sometimes do not show the molecular ion peaks. In addition, undesirable processes such as the molecule’s fragmentation and the formation of multicharged ions cannot be excluded. Only application of more sophisticated and smoother mass-spectrometry techniques can give insight into structural features. However, these are not widely available nowadays yet. An application of diffusivity measurements is very challenging to this end although it has not yet become routine in practical applications.44–49 Namely, a measurement of self-diffusion coefficient (SDC), e.g., by 2D DOSY method that combines the advantages of high-resolution NMR spectroscopy with diffusivity data, could be of use. According to the Einstein-Stokes model the SDC depends on several parameters (eq 1) including an effective hydrodynamic radius (or volume) of the molecule.41,42 Thus, the experimentally measured SDC value can be used to estimate the molecular volume and, doing so, e.g., in the case of such highly symmetrical macrocycles, to count the number of elementary subunits.

SDC )

k BT 6πηRH

(1)

where kB is the Boltzmann gas constant, T (K) is the absolute temperature, η (Pa · s) is the solvent dynamic viscosity, and RH is the hydrodynamic radius of the molecule (m). However, there are intrinsic problems to correlate an experimental self-diffusion coefficient with volume or mass. According to Stokes’ model this coefficient depends on the viscosity of the solvent also. This parameter is difficult to take into account properly because it depends on the solute molecules as well. This problem can be simplified by running measurements at conditions identical to those for model compounds with similar solvating properties to get the relationship between SDC and RH and to use this value for the title compound and thus to get an effective radius from experimental SDC.47–49 In other words,

first we have to “calibrate” the SDC versus radius relationship for known compounds and then to calculate the volume of the unknown compound from its SDC. In our case diamine 3 was chosen as a reference because it represents a simpler fragment of the macrocycle. Its volume was taken as a Solvent-Excluded Volume50 (SEV, Table 1). The SDC values for 1 and 2 were measured under the same conditions and found to be remarkably smaller than for 3 (Table 1). Thus, having SEV (3), SDC (3) and SDC (1), SDC (2), the Vexp value for 1 was estimated as 1757 Å3 and as 1294 Å3 for 2, respectively (for a spherical shape approximation, i.e., V ∼ R3). These values are in reasonable agreement with the corresponding SEVs for 1 and 2 calculated for the tetra-unit macrocycles (see Table 1). The deviation is less than 5% in all cases and it is beyond an error of 20%. At the same time the two nearest SEV values based on 2 and 6 subunits deviate too far from the experimentally determined one (Table 1). An alternative method is based on the empirical relationship between molecular weight and self-diffusion coefficient that was found to be useful in some cases.44–47 This approach is somehow simpler as the molecular weight has a clearer physical meaning for the quantity of subunits in a symmetrical system instead of its molecular volume. Taking into account that for a molecule with a spherical or some other simple geometry R ∼ M-3, molecular weights of 1 and 2 were estimated in a similar way (Table 1). Thus, the overall structures of 1 and 2 can be estimated as having four elementary subunits, as determined from heterocorrelation techniques. This conclusion was supported by X-ray data for 1.29 Conformational Structure and Dynamics of Macrocycles. OWerWiew of Spectral Data. In general, NMR spectra (Figure 3) of compounds 1 and 2 are similar with the exception of the nuclei of the eight-membered ring, which reflects the difference in the structure of the substituents and, probably, different dynamics around the P-Csp2 bond. In 1 rotation around the P-Csp2 bond seems to be slow (on the NMR time scale) and correlation data demonstrate that each Tipp ortho-substituent has two sets of signals (Figure 3a,b). At the same time in the

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Figure 3. 1H NMR spectra of 1 ((a) in CDCl3, (b) in C6D6), 2 ((c) in CDCl3, (d) in C6D6) and 3 ((e) in CDCl3, (f) in C6D6) at T ) 303 K. Impurities marked by (/) DMF, (9) CH3CN, (O) C6H5CH3, (w) H2O, and (b) (CH3)2CO. 1

H NMR spectra of 2 the o-methyl groups have only one set of signals in CDCl3 at room temperature (Figure 3c). In particular, the CH and CH3 protons of the two isopropyl groups at the ortho-position are essentially nonequivalent in the 1 H NMR spectra of 1. Their exact assignment (as in and out51 directed with respect to the macrocycle) has been performed by NOE’s measurements (details in Supporting Information). For the macrocyclic fragments the 1H NMR spectra of 1 and 2 are only slightly different, perhaps due to some difference in conformational structures of these compounds that will be discussed below. Dependence of the Helical Structure on Exocyclic Aromatic Substituents. A computational description of such macrocycles for which dispersion forces are important is currently impossible using ab initio calculations at the post HF level because of the computational expense involved. Therefore, to study the conformations and energies of these systems molecular mechanic methods with the force fields parametrized to reproduce the van der Waals interactions are used. Recent critical evaluation52 demonstrated that, e.g., the MM2 force field performs well in the calculation of aromatic-aromatic interactions, and therefore this computational method was used to analyze structures and energies of possible conformers in solution. The search for low energy structures of macrocycle 1 by MM2 calculations reveals

three stable conformations that are shown schematically in Figure 4. One of them (A) is “cylindrical” and highest in energy. The other two forms (B and C) are helical with different twisting: B is similar to the structure of 1 found in the solid state29 while C is more twisted (Figure 4, as a measure of torsion the angles between the phosphorus-phosphorus axes are used). Indeed, there are a number of observed NOEs between o-iPr (in) and the central phenylene and Me protons for 1 that can be attributed to twisted conformations (B or C) and can hardly be expected if the main form was cylindrical (A) (Figure 5). According to MM2 calculations for 1, the energy difference between the forms B and C is ca. 6 kcal/mol. Taking into account solvent effects both conformers may be well expected in equilibrium in solution. However, a decrease of temperature (up to 233 K) produces no significant changes in the spectrum. Only the signals of the i-Pr groups in the aryls at the exocyclic P atoms sharpened, which was interpreted as slowing down the rate of rotation around the P-Csp2 bonds. Analysis of the B form reveals that in 1 the ortho-substituents (in51 oriented i-Pr) of the aryl group at the exocyclic P atoms are in close proximity to the central phenylene and dimethyl methylene units of the macrocycle. This may prevent stronger twisting of the macrocycle 1 due to steric interactions of these bulky groups or may destabilize the more twisted C form.

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Figure 4. Schematic representation of the main conformers of 1 and 2 with corresponding angles between phosphorus-phosphorus axes and MM2 energies (kcal/mol). Key: N ) blue, P ) violet.

Figure 5. Observed NOEs attributed to the twisted conformation of macrocycle 1.

Therefore, twisting of the macrocycle is not severe (the angle between the phosphorus-phosphorus axes is ca. 65°) and the cavity in the macrocycle in the B form is still large. The most important conclusion from this analysis is that the exocyclic aromatic substituents may play a crucial role in the extent of helical twisting and for the size of the cavity of the macrocycle. This hypothesis initiated an examination if the replacement of the ortho-groups by less bulky ones would allow more twisting of the macrocycle. Indeed, according to MM2 calculations, the replacement of the i-Pr group by Me in the aryl groups at the exocyclic P atoms should modify the conformational equilibrium; the less bulky methyl groups (versus i-Pr) lead to less hindrance of these methyl groups with the

central part of the macrocycle, and the C form in 2 becomes the most stable with an angle between the phosphorus-phosphorus axes of ca. 120°. It is noteworthy that in this C form the volume of the cavity is minimal. It is just this finding, which initiated the synthesis of compound 2 to check the above conclusion. At the same time the B form could also be present in solution because its energy, according to MM2 calculations, is close (ca. 1.1 kcal/mol) to that calculated for C. To verify this finding, we carefully analyzed the NMR data to find indications of such particularities in geometry. For example, for 2 (according to MM2 calculations) the distances between the o-CH3 (in)51 and the central phenylene protons are ca. 7-9, 5-5.5, and 4-4.5 Å in the A, B, and C conformation, respectively. Therefore, in the B and C forms structure-specific NOEs can be expected. However, due to fast rotation around a number of bonds at 243 K there is only one “non-trivial” weak NOE (0.7%) between o-CH3 (in)51 and the central phenylene protons. Taking into account the before-mentioned distances in these conformers this NOE can be attributed to the C form although B can also give some contribution. On the other hand, proton chemical shifts are sensitive to an influence of anisotropic neighboring groups that could also be correlated with their mutual position and used to verify the 3D structure. Therefore, 1H chemical shifts (B3LYP/6-31G(d)// MM2)39 of 1 and 2 were calculated for the three main conformations and then analyzed. Only the protons H8, H9, H13, and Me11 were used as indicative because the chemical shifts of the macrocyclic part should depend mainly on conformational structure (twisting) while the chemical shifts of the exocyclic protons should be influenced strongly by the aryl substituents.

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TABLE 2: Selected Experimental (T ) 303 K) and Theoretical 1H Chemical Shifts (in ppm) of 1 and 2 for Different Conformations B (Twisted), C (Max Twisted), and A (Cyclindrical) 1

2 DFT GIAO//MM2

nucleus angle, deg ∆E, kcal/mol CH3 (C11) H (C8) H (C9) H (C13) Hax (CH2) Heq (CH2)

DFT GIAO//MM2

exp CDCl3 [C6D6]

B [B ⊃ C6H6]

C

A

1.55 [1.66] 6.27 [6.44] 6.91 [6.99] 7.12 [6.65] 4.33 [4.48] 4.44 [4.67]

65 0.0 1.58 [1.47] 5.88 [5.92] 6.65 [6.61] 6.78 [6.09] 3.81 [3.88] 4.02 [4.08]

119 6.2 1.86 6.00 6.78 6.95 3.85 3.99

5 31.7 1.34 6.13 6.86 6.92 3.84 4.10

This is strongly supported by the fact that in the A form, where these protons are not in the proximity to remote anisotropic groups, their chemical shifts should be almost the same in 1 and 2 (Table 2). Comparison of calculated chemical shifts of the diagnostic protons in both compounds shows that in the C form they should resonate at lower field compared to the B form (Table 2). Indeed, experimentally observed changes of 1H chemical shifts (low field shift of several protons of 2 versus 1) by ca. 0.03-0.10 ppm qualitatively support the hypothesis that in 2 the more helical structure is present. Therefore, “edge-to-edge” orientation of the central phenylene groups in the helical structure should lead to low field shifts of their protons. The absolute values and their signs are in general agreement with predicted changes in the chemical shifts in C versus B. Thus, we can conclude that the population of the more twisted C form increases for 2 in comparison with 1. This is also in qualitative agreement with predicted MM2 energies (Figure 4). Dynamic Effects of Exocyclic Aromatic Groups. Details of room temperature 1H NMR spectra of compounds 1 and 2 reflect different dynamics around the P-Csp2 bond in the eightmembered rings due to different bulkiness of the substituents in these compounds. This hypothesis is supported by results of DNMR experiments: for both compounds (1 and 2) the variation of temperature produces dramatic changes for the signals of the exocyclic aromatic groups and only slight changes for other lines (Figure 6). Basically, the coalescence temperatures are different: while in 1 in CDCl3 at T ) 328 K coalescence is observed for the aryl protons H3/5 and the signals of the o-i-Pr protons are about to collapse (due to low bp of CDCl3 it was not possible to increase the temperature), a lower temperature (ca. 278 K) is observed for 2 due to a faster rotation than in 1 (Figure 6). Line shape analysis32 (Figure 6) of the signals of the o-i-Pr and o-Me groups for 1 and 2 allowed us to evaluate the exchange rate constants at different temperatures and then to calculate barriers of rotation around the P-Csp2 bond (Table 3) according to the Eyring’s equation (Supporting Information). To verify if such difference in barriers of rotation around the P-Csp2 bond is a result of the influence of the o-aryl substituents or the interaction of P-aryl substituents with local/remote groups in transition states, theoretical estimation of barriers was carried out for model compounds that mimic the steric situation around these groups in the macrocycles 1 and 2. Model compounds correspond to the heterocycles with an aryl group at one phosphorus atom, with methyl at the another, and with nitrogen atoms bearing methyl (1a and 2a) and phenyl groups (1b and 2b) that model different steric situations at the macrocycles (Figure 7). Starting geometries were obtained by energy optimization of the whole structures of macrocycles 1 and 2, respectively. Then, potential energy profiles of the rotation

exp CDCl3 [C6D6]

B [B ⊃ C6H6]

C

A

1.58 [1.63] 6.31 [6.41] 6.96 [7.00] 7.22 [6.67] 4.44 [4.10] 4.49 [4.49]

56 1.1 1.51 [1.46] 5.91 [5.89] 6.67 [6.59] 6.74 [5.96] 3.86 [3.88] 4.03 [4.12]

119 0.0 1.80 5.90 6.75 6.81 3.92 3.77

4 22.0 1.36 6.13 6.86 6.90 3.95 3.89

around the P-Csp2 bond were calculated by geometry optimization (HF/6-31G) with frozen geometries of the eight-membered ring and around the N-R2 bonds to resemble the local geometry in the macrocycles. According to these calculations the barriers to rotation around the P-Csp2 bonds (Figure 7) in 1a and 2a are 17.0 and 13.4 kcal/mol, respectively. This is in qualitative agreement with experimentally derived values (Table 3). At the same time replacement of the methyl groups at nitrogen by phenyl groups that mimic interaction of these ortho-substituents with the macrocyclic moiety in the transition state essentially increase the calculated barriers for 1b and 2b (45.6 and 23.9 kcal/mol, respectively (Figure 7). Thus, rotational dynamics around the P-Csp2 bond is determined by local steric effects due to different bulkiness of the substituents at the aromatic rings. Moreover, the orientation of the macrocyclic phenylene rings in the transition state seems to be different from the ground state as otherwise a higher barrier should be observed for rotation around the P-Csp2 bond. It seems that rotations around the P-Csp2 bonds and twisting of the macrocycle are someway correlated. Inclusion Phenomenon. Macrocycles attract particular attention due to ability to selectively host different guests inside the cavity.12–20 Most cases12–17 deal with charged species (either “guest” or “hosts” or both) and there are fewer examples of “host-guest” complexes with neutral components (both “host” and “guest”) and only their crystal structures were studied.18–20 Therefore, it was of interest to analyze in solution the macrocycles 1 and 2 also from this point of view, especially, since according to MM2 calculations the low energy conformation of macrocycle 1 exhibits a relatively large cavity where a guest molecule could be included. Moreover, in the solid state (Xray data) a benzene molecules is encapsulated in the macrocyclic cavity demonstrating the ability of 1 to bind large guest molecules in the solid state.26 In the case of aromatic guests their anisotropic effects36,37 on the chemical shifts of the central phenylene protons could be indicative to monitor the aromatic guest position. Indeed, these protons dramatically shift to high field (by 0.48 ppm) when CDCl3 was replaced by C6D6 (Figure 3) although the signals of the same protons in the diamine 3 change only slightly and in the opposite direction (7.09 (CDCl3) vs 7.20 (C6D6) ppm). This is easily explained by the anisotropic effect of the guest benzene because it is oriented in such a way that the protons of the central phenylene group that are directed toward the center of the cavity are shielded by the guest molecule. Moreover, the theoretical value of this effect calculated by semiclassical36,37 and GIAO39 models for the B conformation with a benzene molecule in the cavity (0.72 and 0.70 ppm, respectively) are in qualitative agreement with the experimentally observed chemical shift (0.48 ppm). Thus, NMR investigations of 1 demonstrate that the

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Figure 6. 1H NMR spectra of 1 and 2 in CDCl3 at different temperatures (signals of interest in blue) and simulated spectra (in red) for o-i-Pr and o-Me protons with corresponding exchange rates. Impurities marked by (O) C6H5CH3, (b) (CH3)2CO, (9) CH3CN, (/) DMF, and (w) H2O.

TABLE 3: Barriers of Rotation around the P-Csp2 Bond in 1 and 2

a

compound

∆G#exp, kcal/mol

∆H#exp, kcal/mol

∆S#exp, cal/(mol · K)

∆H#theory, kcal/mol

1 2

16.5 (328 K) 13.4 (283 K)

15.4 11.8

-3.3 -5.6

17.0 (1a)a 13.4 (2a)a

Calculations for models 1a/2a (Figure 7).

supramolecular host-guest complex with an aromatic compound (benzene) situated in the macrocyclic cavity is retained in aromatic solvents. At the same time, for 2 in the most stable conformation C (as observed by MM2 calculations) the macrocyclic cavity is small (Figure 4) and therefore encapsulation of a guest molecule was not expected. However, according to experiments there are analogous high-field shifts for the central phenylene protons in aromatic solvents (∆δ ) 0.55 ppm in C6D6 and 0.61 ppm in

toluene-d8 in comparison with CDCl3) that are even stronger than observed for 1 (0.48 ppm), indicating “host-guest” complex formation. Complexation of macrocycle 2 thta exists predominantly in the twisted C form can be explained by thermodynamic factors. First of all, according to MM2 calculations there is a small energy gap between B and C; therefore, it can be biased in favor of the B form, e.g., due to the solvent effect. Second, an additional stabilization of the B form due to the encapsulation

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Figure 7. Models and potential energy scan of 1a/b and 2a/b along the dihedral angle between the main cycle and aromatic ring plains (rotation around P-Csp2 bonds) at the HF/6-31G level of theory.

of the “guest” can also be expected. For example, according to MM2 calculations there is a remarkable gain in energy for the complexes [1 ⊃ C6H6] and [2 ⊃ C6H6] by 17.2 and 14.8 kcal/ mol, respectively. Therefore, it seems that the energy of specific interactions (e.g., edge-to-face11,53) of the “host” with the “guest” is enough to shift the equilibrium in favor of the B form in benzene and doing so to increase the contribution of the highfield shift of the central phenylene protons. Analysis of the nonequivalent heterocyclic CH2 protons (∆δax-eq ) δax - δeq) additionally supports this hypothesis (Table 2). For 2, there is an essential change in ∆δax-eq when going from CDCl3 to C6D6 (0.05 versus 0.39 ppm, ∆∆δax-eq ) 0.34 ppm) while for 1 there is only a slight effect (0.11 (CDCl3) versus 0.19 ppm (C6D6), ∆∆δax-eq ) 0.08 ppm). According to calculations, variation of ∆δax-eq for 1 when going from the main form (B) to the [B ⊃ C6D6] is ca. 0.01 ppm, while for 2 the ∆∆δax-eq value changes by 0.39 ppm in the C form versus the [B ⊃ C6D6] complex. Thus, for 1 there is no change in population of the two forms and the B form is the major one both in CDCl3 and in C6D6. On the contrary, for 2 the [B ⊃ C6D6] complex becomes dominant only in C6D6. Noticeable slowing of the rotation around the P-Csp2 bond in benzene (toluene) in comparison with CDCl3 (Figure 3d versus Figure 3c) can also be explained by additional stabilization of the ground state in the B form due to complexation with the guest (C6D6) (that leads to an increase of the inversion barrier of the macrocycle itself) while taking into account the conclusion that rotation about the P-Csp2 bonds is correlated with twisting of the macrocycle itself. Conclusion The solution-state structures of highly symmetrical N,Pcontaining macrocycles were established by NMR spectroscopy. The number of magnetically equivalent fragments in such symmetrical macrocycles can be reliably determined by NMR diffusion measurements. According to NOE and GIAO chemical shift data these compounds adopt a helical conformation of the macrocycle. The extent of twisting and the size of the intramolecular cavity of the macrocycle are determined by steric hindrance of substituents of the P-aryl groups with the central Me groups. The macrocycles 1 and 2 form complexes with aromatic hydrocarbons, probably, due to “edge-to-face” dispersion interactions between aromatic groups of “host” and “guest”.

Moreover, the above results demonstrate that in frames of a single NMR method combining different data (chemical shifts, NOE/relaxation, and diffusivity) one may get insight into complicated structural problem in solution. Acknowledgment. This work was supported by the Russian Foundation for Basic Research (grants (No. 09-03-00123-a, 0903-99011), a President of Russia grant for the support of leading scientific schools (grant 3774.2008.03). This investigation was carried out in the NMR department of the federal collective spectral analysis center for physical and chemical investigations of structure, properties, and composition of matter and materials. Supporting Information Available: 1D and 2D NMR spectra, calculated CSs. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry; Wiley: Chichester, U.K., 2000. (2) Rivera, G. D.; Wessjohann, A. L. J. Am. Chem. Soc. 2009, 131, 3721. (3) Gale, A. P.; Garcia-Garrido, E. S.; Joachim, G. Chem. Soc. ReV. 2008, 37, 151. (4) Wang, W.; Shaller, D. A.; Q. Li, D. A. J. Am. Chem. Soc. 2008, 130, 8271. (5) Gloe, K. Macrocyclic chemistry. Current trends and future perspectiVes; Springer: Netherlands, 2005. (6) Bogdan, N.; Condamine, E.; Toupet, L.; Ramondenc, Y.; Bogdan, E.; Grosu, I. J. Org. Chem. 2008, 73, 5831. (7) Alibrandi, G. Angew. Chem., Int. Ed. 2008, 47, 3026. (8) Setsune, J.; Watanabe, K. J. Am. Chem. Soc. 2008, 130, 2404. (9) Cavagnat, D.; Buffeteau, T.; Brotin, T. J. Org. Chem. 2008, 73, 66. (10) Gibson, W. H.; Wang, H.; Slebodnick, C.; Merola, J.; Kassel, W. S.; Rheingold, L. A. J. Org. Chem. 2007, 72, 3381. (11) Katagiri, K.; Tohaya, T.; Masu, H.; Tominaga, M.; Azumaya, I. J. Org. Chem. 2009, 74, 2804. (12) Katayev, A. E.; Boev, V. N.; Myshkovskaya, E.; Khrustalev, N. V.; Ustynyuk, Yu. A. Chem.sEur. J. 2008, 14, 9065. (13) Dubessy, B.; Harthong, S.; Aronica, C.; Bouchu, D.; Busi, M.; Dalcanale, E.; Dutasta, J.-P. J. Org. Chem. 2009, 74, 3923. (14) Pederson, M.-P. A.; Ward, M. E.; Schoonover, V. D.; Slebodnick, C.; Gibson, W. H. J. Org. Chem. 2008, 73, 9094. (15) Zhao, J.-M.; Zong, Q.-S.; Han, T.; Xian, J.-F.; Chen, C.-F. J. Org. Chem. 2008, 73, 6800. (16) Gonzalez-Alvarez, A.; Alfonso, I.; Diaz, P.; Garcia-Espana, E.; Gotor-Fernandez, V.; Gotor, V. J. Org. Chem. 2008, 73, 374. (17) Bernier, N.; Carvalho, S.; Li, F.; Delgado, R.; Felix, V. J. Org. Chem. 2009, 74, 4819.

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