H Chemical Shifts in Two Crystalline Forms of Naproxen - American

Article pubs.acs.org/JPCC

Strong Intermolecular Ring Current Influence on 1H Chemical Shifts in Two Crystalline Forms of Naproxen: a Combined Solid-State NMR and DFT Study Elisa Carignani,†,‡ Silvia Borsacchi,†,‡ Jonathan P. Bradley,§ Steven P. Brown,§ and Marco Geppi*,†,‡ †

Dipartimento di Chimica e Chimica Industriale, Università di Pisa, v. Risorgimento 35, 56126 Pisa, Italy INSTM, Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali, Via G. Giusti 9, 50121 Firenze, Italy § Department of Physics, University of Warwick, Coventry, CV4 7AL United Kingdom ‡

S Supporting Information *

ABSTRACT: The anhydrous crystalline forms of Naproxen [(S)-(+)-2-(6methoxy-2-naphthyl)propionic acid], (NAPRO-A) and its sodium salt (NAPRO-S), widely used anti-inflammatory drugs, have been investigated by means of 1D and 2D MAS NMR and density functional theory (DFT) based calculations. From calculations, 1D 13C CP MAS and 1H CRAMPS and 2D 1H−13C MAS-J-HMQC, refocused INEPT, FSLG-HETCOR, and 1H−1H DQ-CRAMPS solid-state NMR experiments, 1H and 13C resonances have been fully assigned for NAPRO-A and -S. In the case of NAPRO-S, all of the nuclei belonging to the two inequivalent molecules of the asymmetric cell gave rise to distinct signals, which could be completely assigned. Interesting intermolecular ring current effects on 1H chemical shifts have been experimentally observed for the two samples, even if with significant differences between the two cases. The measured and calculated proton chemical shift values showed a very good agreement for both NAPRO-A and -S, allowing us to correlate the different ring current effects with the crystal structures. The comparison between the proton chemical shifts calculated in the crystal structures and in vacuo allowed us to confirm the mainly intermolecular character of the ring current effects and to quantify them.

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INTRODUCTION The elucidation of local structural features of molecules in the solid phase and of their crystal packing is of much interest for all of the applications involving solid systems, from both the chemical synthesis and crystal engineering point of view.1 In the solid state, molecular interactions, ranging from strong hydrogen bonds to weak aromatic σ−π/π−π interactions, have been shown to define the molecular arrangement and consequently the properties of the material. Solid-state nuclear magnetic resonance spectroscopy (SSNMR) has established itself as a technique of primary importance for the investigation of structural properties and intermolecular interactions in solid systems. Moreover, the combination of SSNMR and suitable computational methods is at present a very powerful approach for the characterization of crystalline solids, as proven by the development of “NMR crystallography”.2 Important intermolecular aspects, for which SSNMR provides very detailed information, are the interactions involving the π electron density of aromatic moieties. The ring current effects of the π electron density are known since the beginning of proton NMR. Even if they have been extensively studied, their intermolecular actions in the solid state are still of noticeable interest.3−5 Moreover, the study of ring current effects on proton chemical shifts in the solid state requires very high spectral resolution,6−8 which can be achieved by specific techniques, based on fast magic angle spinning © 2013 American Chemical Society

(MAS) and multiple pulse sequences for homonuclear decoupling,9−13 which are currently continuously improved. Since most drug formulations are solid and different solid forms can show very different properties, the investigation of crystal structure is of particular interest in the pharmaceutical field.14 In the present work we studied two widely used antiinflammatory drugs: the anhydrous crystalline forms of Naproxen [(S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid] (NAPRO-A) and its sodium salt (NAPRO-S). Both the systems have been investigated by means of 1D and 2D 1H and 13C MAS NMR15,16 and DFT GIPAW17,18 calculations. Recently, a study exploiting 23Na solid-state NMR in conjunction with DFT GIPAW calculation on sodium Naproxen and its solvates has also been presented,19 thus confirming the topical interest of this subject. The use of advanced solid-state NMR experiments combined with DFT calculations allowed us to assign all proton and carbon resonances of the two compounds and, in the case of NAPRO-S, the resonances for the two inequivalent molecules in the asymmetric unit. Noticeable intermolecular ring current effects on 1H chemical shifts have been observed for both samples, with varying effects for the different nuclei and the two different solid-state forms. The Received: May 6, 2013 Revised: July 30, 2013 Published: July 30, 2013 17731

dx.doi.org/10.1021/jp4044946 | J. Phys. Chem. C 2013, 117, 17731−17740

The Journal of Physical Chemistry C

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the two molecules and only allowing the hydrogen atoms to move employed a cutoff energy of 1.2 keV and was performed using a Monkhurst-Pack grid with a k-point spacing (upper bound) of 0.1 × 2π Å−1 The optimized geometries are provided as pdb files in the SI. For NAPRO-A, the crystallographic unit cell with Z = 2 and Z′ = 1 (CSD structure code: COYRUD12)42 was used for the calculation; while for NAPRO-S the crystallographic unit cell with Z = 4 and Z′ = 2 (CSD structure code: ASUBUL)43 was used. The calculations of the chemical shielding tensors made use of the gauge-including projector augmented-wave method (GIPAW)17,18 with a cutoff energy of 1.1 keV and was performed using a Monkhurst-Pack grid with a k-point spacing (upper bound) of 0.3 × 2π Å−1. NMR calculations were also performed for an isolated single molecule (referred to as an in vacuo calculation), whereby a molecule was extracted from the geometry-optimized crystal structure and placed into a cubic supercell of dimensions 15 × 15 × 15 Å, where simple cubic (P1) periodicity was reintroduced. A supercell of this size is sufficient to ensure that the calculated isolated molecule chemical shifts have converged for the case here of a moderately sized organic molecule.23

observed ring current effects have been quantified by comparing the 1H chemical shifts calculated in the crystal structures and for isolated molecules corresponding to in vacuo.20−29

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EXPERIMENTAL METHODS Samples. Naproxen acid [(S)-(+)-2-(6-methoxy-2naphthyl)propionic acid] (NAPRO-A) and its sodium salt (NAPRO-S) were both purchased from Sigma-Aldrich Chimica Srl (Milan, Italy) and used as received. NMR Methods. 13C CP MAS and 1H−13C MAS-J-HMQC and HETCOR experiments were performed on a Varian InfinityPlus 400 spectrometer, equipped with 7.5 and 3.2 mm CP MAS probes, working at a Larmor frequency of 399.9 and 100.6 MHz for 1H and 13C, respectively. The 1H 90° pulse lengths were 4.5 and 1.9 μs for the 7.5 and 3.2 mm probe, respectively. A contact time of 1 ms and a spinning frequency of 10 kHz were used for the acquisition of 13C CP MAS spectra, where continuous wave 1H decoupling with a nutation frequency of 42 kHz was used. In the MAS-J-HMQC30 and HETCOR31 2D experiments, FSLG32 and TPPM (nutation frequency of 117 kHz, phase shift of 15°)33 were applied as homonuclear and heteronuclear decoupling sequences, respectively. For MAS-JHMQC experiments, a contact time of 1 ms was used, and the sample was spun at a frequency of 10.127 kHz in order to synchronize the rotation with the pulse sequence. In FSLG-HETCOR experiments, a spinning frequency of 10 kHz and a contact time of 0.5 ms (to limit spin diffusion effects) were used. 1 H MAS and CRAMPS, 1H−13C refocused INEPT,34 1H−1H DQ CRAMPS35 experiments were performed on a Bruker Avance III 500 spectrometer, operating at Larmor frequencies of 500.1 MHz for 1H and 125.8 MHz for 13C, using a 4 mm probe. The 1H and 13C 90° pulse lengths were 2.5 and 5 μs, respectively. High resolution for 1H was achieved using the eDUMBO-122 homonuclear decoupling scheme.36 In 1H DQ experiments, recorded at a MAS frequency of 12.5 kHz, the POST-C737 recoupling method was used at a 1H nutation frequency of 87.5 kHz. In the INEPT experiment, SPINAL6438 was applied as a heteronuclear decoupling sequence; a spinning frequency of 12.5 kHz was used, and 320 transients per row were acquired. 1 H spectra at a MAS frequency of 30 kHz were also acquired on a 2.5 mm triple-resonance probe (operating in double-resonance mode). 1H−1H DQ MAS experiments were also recorded at a MAS frequency of 30 kHz (see the Supporting Information (SI)). For all experiments a recycle delay of 12 and 6 s was used for NAPRO-A and NAPRO-S, respectively. TPPI acquisition mode was used in MAS-J-HMQC and HETCOR 2D experiments, while States-TPPI was used for 2D DQ CRAMPS and refocused INEPT experiments. In all experiments 1H and 13C chemical shifts are referenced to TMS using L-alanine (CH3 peak at 1.1 ppm) and hexamethylbenzene (17.35 and 132.2 ppm) as secondary references, respectively. 1H CRAMPS spectra are referenced and scaled with respect to resolved resonances in 30 kHz MAS spectra. The experimental errors on 13C and 1H chemical shift values are ±0.1 and ±0.2 ppm, respectively. DFT Calculations. DFT calculations were performed using the academic release version 4.3 of the CASTEP39 software package. All the calculations used the PBE exchange-correlation functional40 and ‘‘ultrasoft’’ pseudopotentials.41 A geometry optimization starting with the X-ray single-crystal structures of

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RESULTS AND DISCUSSION C CP MAS and 1H MAS Experiments. In Figure 1, 13C CP MAS spectra of NAPRO-A and NAPRO-S, along with the 13

Figure 1. 13C CP MAS spectra of NAPRO-A (bottom) and NAPRO-S (top) recorded at a 13C Larmor frequency of 100.6 MHz with a spinning frequency of 10 kHz, accumulating 1000 transients. Spinning sidebands are marked with asterisks. The molecular structure of NAPRO-A and the atom numbering used in this work are reported in the inset.

chemical structure of NAPRO-A, are shown. It is possible to easily distinguish the signals of aliphatic (in the region under 55 ppm) and aromatic carbons (region between 100 and 160 ppm), and the signal of carboxylic (NAPRO-A at 179.0 ppm) and carboxylate (NAPRO-S at 183.8 ppm) carbons. As already observed by Di Martino et al.,44 a doubling of the signals at about 17 and 47 ppm is observed for NAPRO-S as compared to the spectrum of NAPRO-A, as expected for the presence of two inequivalent molecules in the crystallographic asymmetric unit. The assignment of the aliphatic spectral region was known for NAPRO-S,44 and it has been easily carried out for NAPRO-A. The signals at about 158 and 104 ppm in both spectra were assigned to nuclei C6 and C7, respectively, due to the inductive deshielding and mesomeric shielding effects of the methoxyl group on C6 and C7 nuclei, respectively. The 1H MAS spectra of NAPRO-A and NAPRO-S, recorded at spinning frequencies of 30 kHz without decoupling and of 17732



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Table 1. 13C and 1H Chemical Shifts (ppm) for NAPRO-A Experimentally Measured (exp) and Calculated (calc) for a Single Molecule in Vacuo (SM) and for the GeometricallyOptimized Crystal Structure (cryst) NAPRO-A calc SMa

calc crysta

exp

124.5 138.6 128.9 130.0 119.0 161.7 102.9 127.7 45.1 178.5 14.6 51.4 130.4 135.3

124.8 136.9 129.6 131.3 118.8 160.8 103.8 129.0 46.9 183.1 14.6 51.8 129.6 134.7

124.0 134.9 129.1 130.6 119.2 158.1 104.3 129.1 47.0 179.0 17.5 53.2 134.9 134.9

7.0 6.7 6.9 6.4 6.4 6.9 3.1 0.8 3.4 6.6

7.1 5.8 4.1 4.9 4.6 5.4 3.3 1.3 2.4 13.6

7.0 6.1 3.8 4.5 4.1 5.9 3.2 1.8 2.3 11.5

13

C nucleus C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 1 H nucleus H1 H2 H3 H4 H5 H6 H7 CH3 OCH3 H14

Figure 2. 1H MAS spectra of NAPRO-A (left) and NAPRO-S (right) at a Larmor frequency of 500.1 MHz. The spectra have been recorded at a spinning frequency of 12.5 kHz with e-Dumbo-122 homonuclear decoupling (bottom) and at a spinning frequency of 30 kHz without decoupling (top), accumulating 32 and 8 transients, respectively.

12.5 kHz with e-Dumbo-122 homonuclear decoupling, are reported in Figure 2. Under 30 kHz MAS, in the case of the sodium form, three peaks can be distinguished, centered at about 0.2, 2.8, and 6.2 ppm, which can be assigned to methyl, methoxyl/methine, and aromatic protons, respectively. In the spectra of the acid form, the signal of the acidic proton resonates at 11.5 ppm; as far as the other 1H nuclei are concerned, three poorly resolved signals can be observed, with maxima at about 1.8, 3.6, and 5.9 ppm, in the MAS spectrum recorded without decoupling. In the spectrum acquired with eDumbo-122 decoupling a better resolution is achieved. The main differences between the two forms concern the chemical shifts of the methyl protons, which are about 1.8 ppm for NAPRO-A and 0.2 ppm for NAPRO-S, and the relative signal intensities between the regions 5−7 ppm (typical of aromatic protons) and 1−5 ppm (typical of aliphatic protons): indeed in the spectrum of NAPRO-A, a greater intensity for signals in the 1−5 ppm region is observed, while the relative intensities of the two regions are inverted in the spectrum of NAPRO-S, thus suggesting that some of the aromatic protons of NAPRO-A resonate at unexpectedly low chemical shifts, between 1 and 5 ppm. DFT-Calculated Chemical Shifts. In order to support the 1 H and 13C peak assignments, mostly performed by the detailed analysis of 2D correlation experiments, and, as will be discussed later, to obtain information about intermolecular ring current effects, the chemical shifts of 1H and 13C nuclei were calculated using the DFT GIPAW method for the molecules in vacuo and in the crystal structure: the results are reported in Tables 1 and 2. The corresponding calculated full chemical shift tensors are reported in the SI. 2D Correlation Experiments. Scalar- and dipolar-based correlation experiments were carried out in order to obtain complementary information. Indeed, MAS-J-HMQC and refocused INEPT sequences, exploiting the through-bond scalar couplings, are valuable tools for the determination of direct connectivities, while the HETCOR experiment, exploiting the through-space dipolar couplings, provides valuable information on the relative spatial arrangements of the atoms within a molecule or of the molecules themselves. Short recoupling times (less than 2 ms) and short spin−echo durations were used in

δiso = −[σiso − σref], where σref (1H) = 30.3 ppm and σref (13C) = 168.7 ppm. a

the MAS-J-HMQC and refocused INEPT experiments, respectively, in order to predominantly observe one-bond connectivities.23 MAS-J-HMQC experiments employing FSLG 1H decoupling were carried out on both NAPRO-A and NAPRO-S. In the case of NAPRO-S, because of the additional spectral complexity due to the presence of two nonequivalent molecules in the crystallographic asymmetric unit, a refocused INEPT experiment with 1H DUMBO homonuclear decoupling, which was observed to provide a better spectral resolution, was also carried out. From the comparison between the MAS-J-HMQC spectrum for NAPRO-A (Figure 3a,b) or the refocused INEPT spectrum for NAPRO-S (Figure 3c,d) and the corresponding 13 C CP MAS spectra, the signals of quaternary carbons can be immediately recognized as those resonating at frequencies higher than 131 ppm, being the only ones that do not give rise to correlation peaks in the 2D spectra. The assignment of 13C and 1H signals for NAPRO-A and NAPRO-S (Tables 1 and 2), discussed in the following in more detail, was performed on the basis of 2D MAS-J-HMQC, refocused INEPT, HETCOR, and DQ-CRAMPS experiments, as well as DFT calculations. The 2D spectrum in Figure 3a,b shows correlation peaks between directly bonded 13C and 1H nuclei in NAPRO-A (correlations are listed in Table 3). The three aliphatic carbons C9, C11, and C12 show correlations with protons resonating at 3.2, 1.8, and 2.3 ppm, respectively. The aromatic carbons show 17733



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Table 2. 13C and 1H Chemical Shifts (ppm) for NAPRO-S Experimentally Measured (exp) and Calculated (calc) for a Single Molecule in Vacuo (SM) and for the GeometricallyOptimized Crystal Structure (cryst)a

Table 3. 1H−13C Correlation Peaks (Chemical Shifts Reported in ppm) Observed in MAS-J-HMQC (NAPRO-A) and INEPT (NAPRO-S) Spectraa NAPRO-S

NAPRO-S

NAPRO-A

calc cryst calc SMb

Mol1

exp

Mol2

Mol1

Mol2

132.4 146.3 121.9 128.6 115.7 159.8 102.4 124.9 45.9 177.0 10.6 51.2 129.7 133.8

131.9 140.9 126.0 132.4 118.6 160.1 105.6 130.7 46.8 185.7 10.6 52.9 129.4 133.7

131.5 137.3 127.3 131.0 118.4 160.0 104.8 126.8 50.7 186.1 18.8 51.6 129.4 134.1

130.1 139.5 123.1 130.1 118.5 157.6 104.4 124.5 48.3 183.8 15.2 53.8 136.5 134.0

129.6 139.5 123.1 129.6 118.5 157.6 104.5 125.5 51.4 183.8 22.2 53.4 136.5 134.0

6.9 6.9 6.9 6.3 6.5 6.9 3.2 0.9 3.4

7.4 5.8 6.6 6.2 5.1 6.5 3.3 −0.4 2.4

5.1 6.4 5.2 4.8 5.8 5.1 2.5 0.6 3.2

7.0 6.0 7.0 6.2 5.3 6.6 3.2 −0.3 2.4

5.4 6.0 5.4 4.7 5.3 5.2 2.5 0.6 3.0

H nucleus

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12

H1

C nucleus

13

C nucleus C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 1 H nucleus H1 H2 H3 H4 H5 H6 H7 CH3 OCH3

13

Mol 1

Mol 2

1

H2 H3 H4 H5 H6 H7 CH3 OCH3

δ13C

δ1H

δ13C

δ1H

δ13C

δ1H

124.0 134.9 129.1 130.6 119.2 158.1 104.3 129.1 47.0 179.0 17.5 53.2

7.0

130.1 139.5 123.1 130.1 118.5 157.6 104.4 124.5 48.3 183.8 15.2 53.8

7.0

129.6 139.5 123.1 129.6 118.5 157.6 104.5 125.5 51.4 183.8 22.2 53.4

5.4

6.1 3.8 4.5 4.1 5.9 3.2 1.8 2.3

6.0 7.0 6.2 5.3 6.6 3.2 −0.3 2.4

6.0 5.4 4.7 5.3 5.2 2.5 0.6 3.0

a

The chemical shifts for carbons and their directly bonded hydrogens are reported in the same line. The assignment of the aliphatic 13C resonances of NAPRO-S was already reported in ref 44.

Table 4. 1H−1H DQ Correlations Expected for NAPRO-A on the Basis of Inter- and Intramolecular H−H Distances from the Geometrically Optimized (CASTEP) Crystal Structurea 1

a

Mol 1 and Mol 2 refer to the two inequivalent molecules present in the crystallographic unit cell. bδiso = −[σiso − σref], where σref (1H) = 30.3 ppm and σref (13C) = 168.7 ppm.

two correlations with protons at about 6−7 ppm (124.0/7.0 ppm, 129.1/5.9 ppm) and three correlations with protons resonating at unusually low chemical shifts: 104.3/4.1 ppm, 119.2/4.5 ppm, and 130.6/3.8 ppm. The 2D spectrum in Figure 3c,d shows correlation peaks between 13C and directly bonded 1H nuclei in NAPRO-S (correlations are listed in Table 3). The extension to a second dimension yields much better resolution as compared to that of the 1D CP MAS spectrum and allows the observation that not only the signals of C9 and C11 carbons, already discussed, but also many other 13C signals are split. The largest chemical shift differences are those of carbons C9 and C11, which give rise to two correlation peaks each 48.3/3.2 and 51.4/2.5 ppm, for C9, and 15.2/−0.3 and 22.2/0.6 ppm, for C11. The carbon of the methoxyl group (C12) also shows two correlations peaks, even if with much smaller differences, at 53.8/2.4 and 53.4/3.0 ppm. For the aromatic carbons, a splitting can be detected only for C8 (124.5 and 125.5 ppm) and the pair of indistiguishable carbons C1 and C4 (130.1 and 129.6 ppm). [The two signals at 130.1 and 129.6 ppm can be safely ascribed to both C1 and C4 in the two inequivalent molecules of NAPRO-S cell mostly on the basis of DFT calculations of the chemical shifts of J-coupled protons.] 1 H−13C FSLG-HETCOR experiments were performed on both the samples. Contrary to the J coupling-based experiment, this dipolar-based sequence allows the spatial proximities to

HA

17734

1

HB

δ(1HB) SQ/ppm

δ (1H) DQ/ppm

5.9 1.8

12.9 8.8

H1 H1

7.0 7.0

H6 CH3

H1 H1

7.0 7.0

OH OCH3

11.5 2.3

18.5 9.3

H2 H2 H3 H3 H4

6.1 6.1 3.8 3.8 4.5

H3 H7 H4 H3 OCH3

3.8 3.2 4.5 3.8 2.3

9.9 9.3 8.3 7.6 6.8

H4

4.5

CH3

1.8

6.3

H5 H5

4.1 4.1

H6 OCH3

5.9 2.3

10.0 6.4

H6

5.9

OCH3

2.3

8.2

H7

3.2

OCH3

2.3

5.5

H7 H7

3.2 3.2

OH CH3

11.5 1.8

14.7 5.0

OH OH

11.5 11.5

OH CH3

11.5 1.8

23.0 13.3

1.8 2.3

3.6 4.6

CH3 OCH3 a

δ(1HA) SQ/ppm

1.8 2.3

CH3 OCH3

HA−HB distance/Å 2.46 2.43, 3.93, 3.48 3.08 3.35, 3.81, 4.98 2.48 2.30 2.48 3.24 2.69, 4.04, 4.25 3.06, 4.14, 4.82 2.47 (3.38) 2.34, 2.33, 3.63 2.52, 4.16, 3.91 2.52, 3.08, 2.49 3.41 2.91, 3.65, 4.33 3.01, 4.14, 3.91 3.12, 3.12 2.96, 4.59, 3.77 3.28, 4.71, 5.02 1.52 1.52

Intermolecular distances are reported in italics. dx.doi.org/10.1021/jp4044946 | J. Phys. Chem. C 2013, 117, 17731−17740


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Figure 3. Aromatic (a) and aliphatic (b) regions of 1H (400 MHz)−13C MAS-J-HMQC 2D spectrum of NAPRO-A recorded at a spinning frequency of 10.127 kHz. 128 rows in the t1 dimension were acquired with an increment of t1 of 34.6 μs, and 216 transients were coadded for each t1 FID. The spin−echo evolution period was 1.38 ms in order to select correlations due to one-bond J couplings. Aromatic (c) and aliphatic (d) regions of 1H (500 MHz)−13C refocused INEPT 2D spectrum of NAPRO-S recorded at a spinning frequency of 12.5 kHz. 94 FIDs in the t1 dimension were acquired with a t1 increment of 34.6 μs, and 320 transients were coadded for each t1 FID. The spin−echo duration evolution period was 1.6 ms. In all the spectra (a-d) the base contour levels are at 20% of the maximum intensity.

be investigated. In the 2D-HETCOR spectra of the two compounds, the most intense correlation peaks were ascribable to directly bonded 1H−13C pairs, thus coinciding with the peaks observed in the MAS-J-HMQC and refocused INEPT spectra. However, several peaks with a lower intensity are evident in the HETCOR spectra, arising from pairs of 1H and 13 C nuclei that are not directly bonded, which were used to perform the assignment of all 13C aromatic resonances (Tables 1 and 2). A 2D HETCOR spectrum of NAPRO-A (Figure 4a,b) shows all of the correlation peaks expected on the basis of the previous considerations, such as those of C10 with the acidic proton (peak at 179.0/11.5 ppm) and with the methyl protons (peak at 179.0/1.8 ppm), and of C6 with H4 and H5 (assigned on the basis of the calculated chemical shifts). Two interesting correlation peaks are those at 124.0/1.8 ppm and 17.5/7.0 ppm that permitted the assignment of the peak at 124.0 ppm to carbon C1. A 2D HETCOR spectrum of NAPRO-S (Figure 4c,d) shows all of the correlation peaks expected in agreement with the previous considerations. Some other peaks proved to be crucial for the assignment of the quaternary aromatic carbons (C2, C13 and C14). The correlations of the carbon resonating at 139.5 ppm with methyl and methine protons (139.5/−0.3 ppm, 139.5/3.0 ppm) allowed the assignment of this signal to carbon C2. The correlation peaks at 136.5/0.6 ppm and 134.0/2.5 ppm led to the assignment of the signals at 136.5 and 134.0 ppm to C13

and C14, respectively, because of the different spatial proximity of the two nuclei to methyl and methoxyl protons, known from the X-ray structure. More detail about the spatial proximity among 1H nuclei is provided by 1H DQ spectra. Specifically, high-resolution 1 H−1H DQ-CRAMPS experiments35 were performed on both the samples. A 2D spectrum of NAPRO-A is shown in Figure 5a: Table 4 lists the DQ peaks expected on the basis of the experimental chemical shifts reported in Table 1 as well as the H−H proximities as extracted from the (geometryoptimized) crystal structure. The correlation peaks shown as red dots in Figure 5a are those corresponding to nuclei with H−H distances shorter than 3.0 Å. Note that correlations corresponding to shorter H−H distances give rise to more intense peaks.45 The analysis of the combination of highresolution 1H−13C and 1H−1H DQ two-dimensional spectra is necessary to assign the C3, C4, and C8 resonances in NAPROA. The calculated 13C chemical shifts (129.0 to 130.6 ppm, see Table 1) alone are too close to ensure a reliable assignment. In the experimental 1H−13C spectrum in Figure 3a, two peaks are observed at (129.1, 5.9 ppm) and (130.6, 3.8 ppm). These two peaks are assigned to both the C8−H6 and C3−H2 (129.1, 5.9 ppm) and the C4−H3 (130.6, 3.8 ppm) one-bond connectivities on the basis of the observed cross peaks due to the H−H proximity of neighboring aromatic protons in the 1H−1H DQ CRAMPS spectrum in Figure 5a: namely, the pairs of cross 17735



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peaks at 7.0 + 5.9 = 12.9 ppm (H1−H6 proximity at 2.46 Å), 5.9 + 4.1 = 10.0 ppm (H6−H5 proximity at 2.47 Å), 6.1 + 3.8 = 9.7 ppm (H2−H3 proximity at 2.48 Å), and 4.5 + 3.8 = 8.3 ppm (H4−H3 proximity at 2.48 Å). Importantly, the 1H−1H DQ CRAMPS spectrum resolves the H2 and H6 resonances at 5.9 and 6.1 ppm that is not possible from the 1H−13C spectrum. A 1H−1H DQ-CRAMPS 2D spectrum recorded for NAPRO-S is shown in Figure 5b, and DQ peaks expected on the basis of the chemical shifts in Table 2 and the H−H proximities are reported in Table 5. As in the case of NAPROA, only correlation peaks due to the dipolar coupling of protons with distances shorter than 3.0 Å are reported in the figure as colored dots. Intermolecular Ring Current Effects. The previous analysis has revealed how several 1H nuclei in both NAPROA and NAPRO-S exhibit surprising chemical shift values. This must be ascribed to solid-state effects and in particular to the magnetic susceptibility of the naphthyl groups of the neighboring molecules, i.e., to an intermolecular ring current shift that affects neighbor spins to different extents depending on the molecular orientation within the crystal lattice. In order to investigate in detail this effect, experimental 1H chemical shifts are compared to those calculated using the GIPAW method both for an isolated single molecule, i.e., corresponding to in vacuo (values not affected by intermolecular ring currents) and in the crystal structure (values affected by intermolecular ring currents), using an approach previously employed in refs 20, 23, 28, 29, and 46−48. An inspection of the X-ray structure of NAPRO-A (Figure 6a) reveals that the molecules are very close to each other and the naphthyl groups of different molecules have an edge-to-face orientation, bringing several 1H nuclei into the shielding cone of the naphtyl ring of neighboring molecules. This is particularly true for the aromatic protons H2, H3, H4, H5, and H6, and for the methoxylic protons, which are those whose vectors joining them with the center of the closest aromatic ring of a neighbor molecule have the shortest moduli and form angles closest to 0° with the normal to the ring plane: all of these protons indeed show unexpectedly low experimental

Figure 4. Aromatic (a) and aliphatic (b) regions of a 2D 1H (400 MHz)-13C FSLG-HETCOR spectrum of NAPRO-A recorded at a spinning frequency of 10.0 kHz. The base contour levels are at 12% and 11.5% of the maximum intensity for panels a and b, respectively. Aromatic (c) and aliphatic (d) regions of 2D 1H (400 MHz)-13C FSLG-HETCOR spectra of NAPRO-S recorded at a spinning frequency of 10.0 kHz. The base contour levels are at 5.5% and 15% of the maximum intensity for panels c and d, respectively. For all spectra, 128 FIDs in the t1 dimension were acquired, coadding 88 transients for each t1 FID. A contact time of 0.5 ms was used. Increments of t1 of (a, b, and d) 31.4 and (c) 15.7 μs were used.

Figure 5. 1H−1H DQ-CRAMPS spectra of (a) NAPRO-A and (b) NAPRO-S, both recorded at a spinning frequency of 12.5 kHz. 160 t1 FIDs were acquired with 16 transients coadded for each t1 FID. Four POST-C7 elements were used for recoupling. In both spectra, the F1 = 2F2 diagonal is shown as a black line. Colored dots indicate the position of the peaks expected on the basis of the experimental chemical shifts reported in Tables 1 and 2 for pairs of 1H nuclei having distances shorter than 3.0 Å (see Tables 4 and 5). In panel b, red, blue, and green dots indicate Mol 1, Mol 2, and Mol 1 − Mol 2 proton pairs, respectively. 17736



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Table 5. 1H−1H DQ Correlations Expected for NAPRO-S on the Basis of Inter- and Intramolecular H−H Distances from the Geometrically Optimized (CASTEP) Crystal Structurea 1

HA

δ(1HA) SQ/ppm

Mol 1 H1

7.0

H1

7.0

H1

7.0

H1

7.0

H2 H2 H2 H2 H3 H3 H3 H3 H4 H4 H5 H5 H6 H6 H6 H6 a

6.0 6.0 6.0 6.0 7.0 7.0 7.0 7.0 6.2 6.2 5.3 5.3 6.6 6.6 6.6 6.6

δ(1HB) SQ/ppm

1

HB

H7 (mol H6 (mol H2 (mol H7 (mol H3 (mol CH3 (mol H6 (mol H3 (mol H4 (mol H5 (mol H4 (mol H6 (mol H5 (mol OCH3 (mol H6 (mol OCH3 (mol H2 (mol H3 (mol H1 (mol H7 (mol

δ(1H) DQ/ ppm

HA−HB distance/Å

3.2

10.2

2.35

6.6

13.6

2.46

6.0

13.0

3.04

2.5

9.5

3.22

1

1) 1)

HA

H7

3.2

OCH3

2.4

CH3 Mol 2 H1

1)

δ(1HA) SQ/ppm

−0.3

5.4

2) 7.0

13.0

H1

2.46

5.4

1) 1)

−0.3

5.7

6.6

12.6

H1

2.24, 2.78, 3.74 2.61

H2

5.4 6.0

1) 5.4

11.4

3.35

H2

6.0

2) 6.2

13.2

H2

2.49

6.0

1) 5.3

12.3

2.94

H3

5.4

1) 4.7

11.7

2.78

H3

5.4

2) 6.6

13.6

2.90

H4

4.7

1) 5.3

11.5

3.27

H5

5.3

1) 3.0

9.2

2) 6.6

11.9

3.60, 3.94, 5.8, 3.75, 4.12, 5.15 2.47

H5 H5

5.3 5.3

1) 2.4

7.7

2.22, 2.39, 3.60

H5

5.3

1) 6.0

12.6

2.61

H7

2.5

1) 7.0

13.6

2.90

1) 5.4

12

2.80

2) 2.5

9.1

OCH3

3.0

CH3

0.6

δ(1HB) SQ/ppm

1

HB

CH3 (mol 1) OCH3 (mol 1) CH3 (mol 1) H7 (mol H6 (mol H6 (mol H3 (mol CH3 (mol H6 (mol H4 (mol H5 (mol OCH3 (mol H6 (mol OCH3 (mol OCH3 (mol H3 (mol CH3 (mol OCH3 (mol CH3 (mol

δ(1H) DQ/ ppm

HA−HB distance/Å

−0.3

2.9

2.43, 2.57, 3.07

2.4

4.8

1.52 (within CH3)

−0.3

−0.6

2.7

8.1

2.31

5.2

10.6

2.47

5.2

10.6

2.80

5.4

11.4

2.48

0.6

6.6

5.4

11.4

3.34

4.7

10.1

2.47

5.3

10.7

3.29

1.52 (within OCH3)

2) 2) 2) 2) 2.13, 3.11, 3.72

2) 2) 2) 2) 3

7.7

2.62, 4.04, 4.37

2) 5.2

10.5

2.51

2) 3

8.3

2.28, 2.33, 3.60

2.4

7.7

2.88, 3.46, 4.46

5.4

10.7

0.6

3.1

2.50, 2.50, 3.08

3.0

6.0

1.52 (within CH3)

0.6

1.2

1.52 (within OCH3)

2) 1) 3.29

2) 2) 2) 2)

2.77

2)

Intermolecular distances are reported in italics.

possible to observe that the 1H nuclei within the shielding cone of the neighboring aromatic rings are H2, H5, methoxyl, and methyl protons for Mol 1 and H1, H3, H4, and H6 for Mol 2. Therefore, it is expected that in the two inequivalent molecules, complementary sets of protons are exposed to intermolecular shielding effects. This is confirmed by both experimental and calculated data. As for NAPRO-A, the agreement between experimental and calculated (in the crystal) 1H chemical shift values is very good, with a maximum deviation of 0.5 ppm, and an average deviation of 0.2 ppm. The comparison between the two sets of calculated chemical shift values reveals shifts of −1.4, −1.3, −1.1, and −1.0 ppm for H5, CH3, H2, and OCH3 protons, respectively, in Mol1 and −1.8, −1.8, −1.7, and −1.5 ppm for H1, H6, H3, and H4, respectively, in Mol 2. This indicates that the ring current effect is slightly stronger for Mol 2 protons than for Mol 1 ones. This effect is quantitatively comparable with that exhibited by NAPRO-A, for which, however, the largest shielding shift is observed (−2.8 ppm for H3).

chemical shift values. The agreement between experimental and calculated (in the crystal) chemical shifts is very good, with a maximum deviation of 0.5 ppm, and an average deviation of 0.3 ppm, with this observation being consistent with other GIPAW calculations of 1H chemical shifts.20,23,29,49−51 This allows us to use the comparison between the two sets of calculated chemical shifts (in vacuo and in the crystal) as a measure of the intermolecular effects due to the crystal packing. Indeed, apart from the acidic proton, which is obviously dramatically affected by the presence of neighboring molecules, due to the formation of strong hydrogen bonds,20,23,28 all the other protons showing noticeable differences between the two calculated values are those located within the shielding cone of neighboring aromatic rings, listed above. In particular, H3, H5, H4, H6, OCH3, and H2 show shifts of −2.8, −1.8, −1.5, −1.5, −1.0, and −0.9 ppm, respectively, with respect to their calculated values in vacuo, H3 being the most affected nucleus. In NAPRO-S, the situation is more complex due to the presence of two inequivalent molecules in the crystallographic cell. From the crystal structure (Figure 6b), it is however 17737



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obtained by calculation using DFT techniques based on the GIPAW method. Interestingly, the influence of intermolecular interactions on the 1H chemical shifts, due to the crystal packing, is marked not only for the acidic protons in NAPROA, involved in strong hydrogen bonds, but also for several other 1 H nuclei. In particular, many aromatic and aliphatic protons showed a surprising shielding, up to 3 ppm, due to intermolecular ring current effects, originating from the aromatic rings of neighboring molecules. These effects could be explained with the peculiar edge-to-face arrangement of the aromatic moieties in the crystalline forms of both NAPRO-A and NAPRO-S.

■

ASSOCIATED CONTENT

S Supporting Information *

(i) Calculated (GIPAW) chemical shift tensors for NAPRO-A and NAPRO-S; (ii) 1H DQ MAS (30 kHz) spectra of NAPROA and NAPRO-S (pdf); (iii) Geometry-optimized (CASTEP) structures of NAPRO-A and NAPRO-S (pdb). This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*Telephone: +39-0502219289. Fax: +39-0502219260. E-mail: [email protected]; Web site: www.dcci.unipi.it/∼mg. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Funding from Engineering and Physical Sciences Research Council (EPSRC) and AstraZeneca is acknowledged. The 500 MHz solid-state NMR spectrometer at the University of Warwick used in this research was funded through the Birmingham Science City Hydrogen Energy project, with support from Advantage West Midlands. CASTEP calculations were performed the University of Warwick Centre for Scientific Computing cluster. S.P.B. is grateful to Accelrys for providing the Materials Studio Interface.

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REFERENCES

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Figure 6. Representations of the orientation of neighboring molecules in the geometry-optimized crystal structures of (a) NAPRO-A and (b) NAPRO-S. Geometrical optimization started from the CSD structures42,43 only allowing the hydrogen atoms to move. In panel b, the two inequivalent molecules are indicated as Mol 1 and Mol 2. In both panels a and b, the protons experiencing noticeable shielding effects due to intermolecular ring current are highlighted with blue circles. The angles between the normal to the ring plane and the vectors joining highlighted protons with the center of the closest ring of a neighboring molecule are drawn. The geometrical parameters can be found in the .pdb files available as SI.

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CONCLUSIONS The variety of one- and two-dimensional SSNMR techniques employed here, along with DFT calculations, allowed us to completely assign the 1H and 13C resonances of the acidic (NAPRO-A) and Na-salt (NAPRO-S) forms of Naproxen in the solid state. In particular, in NAPRO-S, individual assignments could be carried out for each nucleus of the two inequivalent molecules present in the crystallographic cell. Excellent reproduction of the experimental chemical shifts was 17738



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H Chemical Shifts in Two Crystalline Forms of Naproxen - American

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