Hydrogen Bonds in Cocrystals and Salts of 2-Amino-4,6

Article pubs.acs.org/JPCB

Hydrogen Bonds in Cocrystals and Salts of 2‑Amino-4,6dimethylpyrimidine and Carboxylic Acids Studied by Nuclear Quadrupole Resonance Janez Seliger*,†,‡,§ and Veselko Ž agar† †

“Jozef Stefan” Institute, Jamova 39, 1000 Ljubljana, Slovenia Faculty of Mathematics and Physics, University of Ljubljana, Jadranska 19, 1000 Ljubljana, Slovenia § EN-FIST Centre of Excellence, Dunajska 156, 1000 Ljubljana, Slovenia ‡

ABSTRACT: 14N and 17O nuclear quadrupole resonance frequencies have been measured in 1:1 cocrystals and salts of 2-amino-4,6-dimethylpyrimidine and several carboxylic acids. A systematic decrease of the 17O quadrupole coupling constant on increasing strength of the hydrogen bond is observed in cocrystals bound by O−H···N hydrogen bonds. The O−H distances deduced from the line widths of the 17O NQR lines show that the hydrogen atom is in a hydrogen bond formed by a carboxylic groups for about 0.01 nm displaced from the oxygen atom toward the center of the hydrogen bond. In the O−H···N hydrogen bond formed by the hydroxyl group, which is only slightly longer than the hydrogen bonds formed by the carboxyl group, the hydrogen atom is much less displaced. A linear relation between the 14N quadrupole coupling constant and the sum of the inverse third powers of the H···A (A = O or N) distances is deduced for the amino group. A linear correlation of the principal values of the 14N quadrupole coupling tensor in −NH2, as observed in the solid phase and in the gas phase, is analyzed in a simple model assuming a displacement of the electron charge in the N−H σ bond and simultaneous deformation of the nitrogen lone pair electron orbital. At the ring nitrogen position, hydrogen bonding and proton transfer produce a large decrease of the 14 N quadrupole coupling constant. A linear correlation of the principal values of the 14N quadrupole coupling tensor is observed in cocrystals and salts of 2-amino-4,6-dimethylpyrimidine. This correlation differs from the correlation observed in substituted pyrimidine, where the hydrogen atoms are replaced by other atoms or functional groups. The difference is analyzed in a model, which assumes that the hydrogen bonding and substituents affect the nitrogen lone pair and π electron orbitals. The analysis shows that the two effects are nearly independent.

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INTRODUCTION Molecular recognition plays an important role in biological systems and in artificial supramolecular systems. It refers to the specific interaction between two or more molecules through noncovalent bonding such as hydrogen bonding, hydrophobic forces, van der Waals forces, π−π interactions, etc. The formation of supramolecular assemblies is related to the positions and properties of functional groups in the molecules. A detailed knowledge of functional groups in molecules is necessary to understand the intermolecular bonding in these systems. The same is true in the formation of a cocrystal with desired structural features and macroscopic properties. Cocrystal is a nonionic supramolecular complex, which is constructed through several types of interaction, including hydrogen bonding, π−π stacking, and van der Waals forces.1−6 In a cocrystal, homosynthons and heterosynthons generally occur. Their occurrence depends on the molecular architecture and the positions and properties of functional groups. Pyrimidines and aminopyrimidine derivatives are biologically important compounds that manifest themselves in nature as components of nucleic acids. The functions of nucleic acids are explicitly determined by hydrogen-bonding patterns including base pairing, which is responsible for genetic information transfer. Their interactions with carboxylic acids are involved in © 2013 American Chemical Society

protein−nucleic acid recognition and drug−protein recognition processes. Cocrystals of aminopyrimidine with carboxylic acids represent model systems where the hydrogen-bonded supramolecular motifs can be studied in details.7 Nuclear quadrupole resonance (NQR) presents a view of the electron charge distribution in the part of the molecule where the quadrupole nucleus is located. Nitrogen and oxygen atoms are of particular importance in numerous biologically and pharmaceutically important compounds. Each of the two atoms acts either as a hydrogen-bond donor or as a hydrogen-bond acceptor. Their NQR frequencies depend on the population of the electron orbitals and represent a sensitive tool for the study of hydrogenbond strength and the position of proton within the hydrogen bond.8 It has been recently shown how 14N NQR can be used to prove that a cocrystal is formed, to characterize the cocrystal and to distinguish between crystal polymorphs.9,10 Sharp 14N NQR lines at the frequencies different from those in the cocrystal formers prove that the cocrystal is indeed formed. The complete set of the 14N NQR frequencies uniquely characterizes a Received: April 12, 2013 Revised: May 15, 2013 Published: May 15, 2013 6946

dx.doi.org/10.1021/jp403617e | J. Phys. Chem. B 2013, 117, 6946−6956

The Journal of Physical Chemistry B

Article

structural parameters. A deeper insight into the relation between the NQR parameters on one side and electron distribution, molecular structure, and intermolecular interactions on the other side is obtained by the quantum chemical (DFT) calculations. Here, the NQR frequencies are calculated on the basis of a known or proposed crystal structure, and these theoretical results are compared to the experimentally determined NQR frequencies.15−19

cocrystal. When crystal polymorphs are formed, they differ in the 14 N NQR spectrum. In an aminopyrimidine molecule (Figure 1), there are two ring nitrogen atoms acting as the hydrogen-bond acceptors and the

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Figure 1. Structural formula of 2-aminopyrimidine and numbering of ring positions.

N AND 17O NQR The nuclear isotopes 14N and 17O have in their ground states spins I = 1 and I = 5/2, respectively, and nonzero nuclear electric quadrupole moments. The interaction of a nuclear electric quadrupole moment with the surrounding inhomogeneous electric field is described by the Hamiltonian HQ:20

amino (−NH2) group, which acts as the hydrogen-bond donor. When aminopyrimidine interacts with a carboxylic acid, the molecules form N···H−O and N−H···O hydrogen bonds as shown in Figure 2. In some cases, proton transfer occurs from the hydrogen-bond donor (O1H) to the hydrogen-bond acceptor (N1).

14

HQ =

eQVZZ ⎛ 2 ⎞ η 2 ⎜3I − I (I + 1) + (I+ + I −2)⎟ z ⎝ ⎠ 4I(2I − 1) 2

(1)

Here, eQ is the nuclear electric quadrupole moment, and VZZ is the largest principal value of the electric field gradient (EFG) tensor Vik, Vik = ∂2V/∂xi∂xk, composed of the second derivatives of the electrostatic potential V with respect to the coordinates. The symmetric traceless second rank EFG tensor has three principal values named VXX, VYY, and VZZ (|VZZ| ≥ |VYY| ≥ |VXX|), which are usually described by two parameters: the largest principal value VZZ and the asymmetry parameter η of the EFG tensor defined as η = (VXX − VYY)/VZZ. The values of the asymmetry parameter η range between 0 and 1. A 14N nucleus exhibits in zero external magnetic field three generally nonequidistant and nondegenerate nuclear quadrupole energy levels. The transition (NQR) frerquencies between these energy levels depend on quadrupole coupling constant e2qQ/h = |eQVZZ/h| and the asymmetry parameter η as

Figure 2. Hydrogen bonds between 2-aminopyrimidine and carboxylic acid and numbering of nitrogen and oxygen positions.

2-Amino-4,6-dimethylpyrimidine (AMP) is known to form cocrystals or salts with several carboxylic acids including malonic acid (MA),7 5-chlorosalicylic acid (5CSA),7 benzoic acid (BA),11,12 4-hydroxybenzoic acid (4HBA),13 and anthranilic acid (AA).14 In the present study, we show that it forms a salt also with oxalic acid (OA). The structural formulas of these carboxylic acids are presented in Figure 3.

ν+ =

e 2qQ (3 + η) 4h

ν− =

e 2qQ (3 − η) 4h

ν0 = ν+ − ν− =

e 2qQ η 2h

(2) 14

Here, h is the Planck constant. From the N NQR frequencies, the quadrupole coupling constant and the asymmetry parameter η are calculated as e 2qQ 2 = (ν+ + ν−) h 3

Figure 3. Structural formulas of carboxylic acids used in the present study to form 1:1 cocrystals and salts with 2-amino-4,6-dimethylpyrimidine.

η=

3(ν+ − ν−) ν+ + ν−

(3)

17

O, the only magnetically active stable oxygen isotope, has a natural abundance of 0.037%. In zero magnetic field, a 17O nucleus exhibits three doubly degenerate nuclear quadrupole energy levels. Their energies are calculated from the secular equation:20

We synthesized the previously mentioned cocrystals and salts of 2-amino-4,6-dimethyl pyrimidine and carboxylic acids. In all substances, we have measured the 14N NQR frequencies. In selected cocrystals, we have measured also the 17O NQR frequencies and line widths. In this Article, we present the experimental results and an analysis of these results, which may elucidate some details of hydrogen bonding, especially the proton position within the bonds and the hydrogen-bond influence on bonding and nonbonding electron orbitals. We base our discussion on various correlations between the NQR and

x 3 − 7(3 + η2)x − 20(1 − η2) = 0

(4)

Here, an energy E is expressed as E = (eqVZZ/20)x, where x is a solutionn of the secular equation. The three 17O NQR frequencies are usually marked as ν5/2−1/2 > ν5/2−3/2 ≥ ν3/2−1/2. 6947



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irradiation.26,27 These techniques are based on magnetic field cycling. The details of the present experimental setup and the measuring procedure are published in a previous paper.28 The 17O quadrupole coupling constant and asymmetry parameter η can be obtained either by NMR or by NQDR. In NMR, the frequency distribution of the central, 1/2 ↔ −1/2, transition line in a powder sample under MAS is used to extract the NQR parameters. In the present study, we used Slusher and Hahn’s NQDR technique 29 and NQDR with coupled multiplets22 to measure the 17O NQR frequencies in naturally abundant samples. The details of the experimental setup and experimental procedure are described in a previous paper.24

They uniquely depend on the quadrupole coupling constant e2qQ/h = |eQVZZ/h| and the asymmetry parameter η. The asymmetry parameter η is calculated from the ratio R = ν3/2−1/2/ ν5/2−3/2, which monotonously changes from R = 0.5 at η = 0 to R = 1 at η = 1. When η is known, the absolute value of the 17O quadrupole coupling constant can be calculated from any 17O NQR frequency. The principal values of the EFG tensor cannot be determined by NQR. What can be determined by NQR are the absolute principal values of the quadrupole coupling tensor qik, qik = eQVik/h, but the present knowledge of the nuclear electric quadrupole moments eQ21 can be used to calculate the absolute principal values of the EFG tensor from the NQR data. The sign of the quadrupole coupling tensor cannot be determined by NQR. Other experiments, for example, microwave spectroscopy, are necessary for this purpose. The smallest principal values qXX and qYY of the quadrupole coupling tensor are related to the largest (by magnitude) principal value qZZ and the asymmetry parameter η as 1 qXX = − qZZ (1 − η) 2 1 qYY = − qZZ (1 + η) 2

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EXPERIMENTAL RESULTS Solid-effect 1H−14N NQDR spectra of two characteristic samples, 2-amino-4,6-dimethylpyrimidine−benzoic acid (1:1) and 2-amino-4,6-dimethylpyrimidine−malonic acid (1:1), measured in low magnetic field B = 2.35 mT (νH = 100 kHz), are presented in Figure 4. The duration of the relaxation period was

(5)

In case of an O−H group, each doubly degenerate 17O nuclear quadrupole energy level splits due to the dipolar interaction with the nearest proton (S = 1/2) into a quartet of energy levels. The 17 O NQR lines become broad and structured. Double resonance with coupled multiplets22 is used to measure the width and structures of the three 17O NQR lines. From the widths and structures of the 17O NQR lines, it is possible to determine the O−H distance, the sign of the 17O quadrupole coupling constant, and the orientation of the O−H bond in the principal axes frame of the EFG tensor.23,24 The procedure of determination of the O−H distance from the 17O NQR line widths is as follows. First, the asymmetry parameter η is calculated from the NQR frequencies. At this value of η, we numerically calculate23 the widths of the three 17O NQR lines as functions of the angle θ between the principal axis Z of the EFG tensor and the direction of the O−H bond. The O−H distance is taken equal to 0.100 nm in this calculation. We then calculate the ratio (Δν)5/2−3/2/ (Δν)3/2−1/2 as a function of θ and compare it to the experimentally determined ratio. In such a way, we determine the angle θ. The third root of the ratio (Δν)3/2−1/2)calc/ ((Δν)3/2−1/2)exp taken at the known value of θ multiplied by 0.100 nm is equal to the O−H distance. The width of the highest frequency 17O NQR line, if it can be measured, is used to check the calculations.

Figure 4. Solid-effect 1H−14N NQDR spectra of cocrystal 2-amino-4,6dimethylpyrimidine−benzoic acid and salt 2-amino-4,6-dimethylpyrimidine−malonic acid measured in the low magnetic field B = 2.35 mT. The NQR frequencies from the nitrogen positions observed in the NQDR spectra are denoted on the frequency scales.

set to 0.5 s. The amplitude of the rf magnetic field was approximately equal to 3 mT. In both spectra, we observe strong level-crossing and solid-effect lines from the −NH2 nitrogen position. The level-crossing lines are observed at the 14N NQR frequencies ν0 = 670 kHz, ν− = 2110 kHz, ν+ = 2780 kHz in 2amino-4,6-dimethylpyrimidine−benzoic acid (1:1) and at ν0 = 890 kHz, ν− = 1630 kHz, ν+ = 2520 kHz in 2-amino-4,6dimethylpyrimidine−malonic acid (1:1). These NQR frequencies are denoted as 1 on the frequency scale. The solid-effect lines are observed at the frequencies ν0 + νH, ν0 + 2νH, ν− + νH, ν+ ± νH, and ν+ + 2νH in both compounds. The solid-effect lines that are shifted for 2νH from the NQR frequencies are characteristic for a nitrogen nucleus interacting with a strongly coupled pair of protons, that is, for the −NH2 group in the present case. In the NQDR spectrum of 2-amino-4,6-dimethylpyrimidine−malonic acid (1:1), we observe weaker, but still relatively strong, levelcrossing and solid-effect lines around the NQR frequencies denoted by 2 (450 kHz, 1070 kHz, 1520 kHz). The 14N−1H dipolar interaction is in this case strong, so these lines correspond to the N1−H+ nitrogen position in the N1−H+···O hydrogen bond, where the hydrogen nucleus is transferred from the hydrogen-bond donor to the hydrogen-bond acceptor. The second nitrogen position (N3) in the pyrimidine ring, which is involved in a weaker hydrogen bond, is not observed in the solideffect NQDR spectrum. In the NQDR spectrum of 2-amino-4,6dimethylpyrimidine−benzoic acid (1:1), we observe in addition

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EXPERIMENTAL PROCEDURE The samples of 2-amino-4,6-dimethylpyrimidine, oxalic acid, malonic acid, 5-chlorosalicylic acid, benzoic acid, 4-hydroxybenzoic acid, and anthranilic acid were purchased at SigmaAldrich and used as obtained. The cocrystals were obtained by mixing hot methanol solutions of cocrystal formers. The solutions were then left at room temperature until the cocrystals grew from the solution. The 14N NQR frequencies are usually measured either by pulsed NQR or by 1H−14N nuclear quadrupole double resonance (NQDR). In the present study, we have used several NQDR techniques including the solid-effect technique25 and the technique using multiple frequency sweeps and two-frequency 6948



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to the strong NQDR lines from the −NH2 nitrogen position also a set of much weaker NQDR lines around the 14N NQR frequencies 700, 1600, and 2300 kHz. These NQR frequencies may be assigned to the N1···H−O nitrogen position where the pyrimidine ring nitrogen atom participates in a short hydrogen bond. The weakly hydrogen-bonded ring nitrogen position N3 is again not seen in the solid-effect NQDR spectrum. The accuracy of determination of the 14N NQR frequencies by this technique is ±10 kHz. From a single solid-effect NQDR spectrum, it is often not possible to unambiguously assign the lines. To determine which lines are the level-crossing lines and which lines are the solideffect lines, we have measured the solid-effect NQDR spectra at different values of νH. The above conclusions are the result of an analysis of several solid-effect NQDR spectra for each compound. The missing 14N NQR frequencies from the nitrogen ring position N3 have been determined using multiple frequency sweeps and two-frequency irradiation. The experimental spectra of 2-amino-4,6-dimethylpyrimidine−malonic acid are presented in Figure 5. The experiment consisted of three steps. First, the

performed a precise measurement of the 14N NQR frequencies ν− and ν+ by the two-frequency irradiation (Figure 4d and e) and obtained two dips centered at 2353 kHz (ν−) and 2823 kHz (ν+). The two rf magnetic fields were applied during the relaxation period as a series of repetitive pulses with the frequencies ν1 and ν2. The duration of a pulse was set to 1 ms, and the amplitudes of the two rf magnetic fields were approximately 0.2 mT. By the above techniques, we determined the 14N NQR frequencies in 2-amino-4,6-dimethylpyrimidine at room temperature and in (1:1) cocrystals and salts made of 2-amino-4,6dimethylpyrimidine and benzoic acid, 4-hydroxybenzoic acid, anthranilic acid, 5-chlorosalycylic acid, malonic acid, and oxalic acid. The 14N NQR frequencies at all nitrogen positions were precisely determined by the two-frequency irradiation technique. The 14N NQR frequencies in 2-amino-4,6-dimethylpyrimidine30 and anthranilic acid31 have previously been determined at T = 77 K. We performed the measurements in 2-amino-4,6-dimethylpyrimidine at a different temperature to check for the possible strong molecular motions and phase transitions. The 14N NQR frequencies, quadrupole coupling constant, and the asymmetry parameter η of the above compounds are summarized in Table 1. The 17O NQR frequencies have been measured in naturally abundant cocrystals made of 2-amino-4,6-dimethylpyrimidine and anthranilic acid, 4-hydroxybenzoic acid, and benzoic acid. In these compounds, the hydrogen atoms are located at the donor (O−H) position in the O1−H···N1 hydrogen bonds. The short O−H distance makes the 1H−17O dipole−dipole interaction Table 1. 14N NQR Frequencies, Quadrupole Coupling Constant e2qQ/h, and Asymmetry Parameter η in 2-Amino4,6-dimethylpyrimidine (AMP) and Cocrystals Made of AMP and Anthranilic Acid (AMP-AA), 4-Hydroxybenzoic Acid (AMP-4HBA), Benzoic Acid (AMP-BA), 5-Chlorosalicylic Acid (AMP-5CSA), Malonic Acid (AMP-MA), and Oxalic Acid (AMP-OA) substance AMP30

AMP

Figure 5. Determination of 14N NQR frequencies from the nitrogen position N3 in the pyrimidine ring in 2-amino-4,6-dimethylpyrimidine− malonic acid (1:1). The details are presented in the text.

AMP-AA

lowest 14N NQR frequency ν0 was determined by performing the νH scan under the influence of multiple frequency sweeps of an rf magnetic field with the sweep frequency limits νmin = 2 MHz and νmax = 4 MHz and with the sweep duration 10 ms. The duration of the relaxation period was set to 0.5 s. The amplitude of the rf magnetic field was approximately 2 mT. We observe a strong dip at νH = ν0 = 480 kHz and a weaker and narrower dip at νH = ν0/2 = 240 kHz (Figure 4a). In addition, we observe a weak cross relaxation dip at νH = 890 kHz corresponding to the −NH2 nitrogen position. In the second step, the proton NMR frequency was fixed at νH = ν0 = 480 kHz, and the two upper 14N NQR frequencies ν− and ν+ were located by varying the sweep frequency limits νmin and νmax. Sharp increases of the proton NMR signal are observed at νmin = 2350 kHz and νmax = 2820 kHz (Figure 4b and c), so the upper 14N NQR frequencies ν− and ν+ are approximately equal to these values. In the third step, we

AMP4HBA AMP-BA

AMP5CSA AMPMA AMP-OA

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nitrogen position N1, N3 N3, N1 N2 N1, N3 N3, N1 N2 N3 N1 N2 N4(AA) N3 N1 N2 N3 N1 N2 N3 N1H+ N2 N3 N1H+ N2 N3 N1H+ N2

T (K) 77

295

180

295

295

295

295

180

ν+ (kHz)

ν− (kHz)

e2qQ/h (kHz)

η

2747.6 2732.3 2948.1 2727 2728 3010 2760 2423 2935 2680 2555 2482 2936 2765 2297 2775 2852 1570 2440 2823 1520 2515 2877 1470 2520

2423.0 2409.6 2483.7 2449 2433 2370 2432 1852 2203 1927 2075 1913 2261 2415 1601 2107 2438 1085 1575 2353 1075 1625 2432 890 1660

3447.1 3427.9 3621.7 3451 3441 3587 3461 2850 3425 3071 3087 2930 3465 3453 2599 3255 3527 1770 2677 3451 1730 2760 3539 1573 2787

0.1883 0.1883 0.2565 0.161 0.171 0.357 0.190 0.401 0.427 0.490 0.311 0.384 0.390 0.203 0.536 0.410 0.235 0.548 0.646 0.278 0.514 0.645 0.251 0.737 0.617



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Table 2. 17O NQR Frequencies, Quadrupole Coupling Constant e2qQ/h, Asymmetry Parameter η, and OH Distances ROH in Cocrystals Made of 2-Amino-4,6-dimethylpyrimidine and Anthranilic Acid, 4-Hydroxybenzoic Acid, and Benzoic Acida substance AMP-AA

AMP-4HBA AMP-BA a

oxygen position

ν3/2−1/2 (kHz)

ν5/2−3/2 (kHz)

O1 O2 O1 O2 hydroxyl O1 O2

1125 (80) 1290 (−) 1110 (80) 1250 (−) 1580 (100) 1040 (75) 1270 (−)

ν5/2−1/2 (kHz)

e2qQ/h (kHz)

η

ROH (nm)

2190 (75)

7330

0.146

0.110 ± 0.003

2180 (75)

7290

0.120

0.110 ± 0.003

8550 6880

0.488 0.087

0.102 ± 0.002 0.112 ± 0.003

4040 (105) 2060 (70)

The numbers in brackets represent the dipolar widths of the 17O NQR lines, from which the OH distances ROH are calculated.

position. The qcc dependence of the 17O NQR frequencies ν5/2−3/2 and ν3/2−1/2, as calculated using expression 6, is presented in Figure 6. The 17O NQR frequencies at the OH positions given

strong, which increases the sensitivity of detection of rather weak 1 H−17O NQDR lines. Additionally, this interaction broadens the 17 O NQR lines, which can be used to determine the O−H distance. The NQDR techniques we used involve magnetic field cycling between a high (0.75 T) and zero magnetic field. To get in zero magnetic field with long enough proton spin−lattice relaxation time (∼1 s), we cooled the samples to T = 183 K. We first made a frequency scan by a square wave phase modulated rf magnetic field.29 The modulation frequency was 1.5 kHz, and the amplitude of the rf magnetic field was 4 mT. We then made a two-frequency scan with the frequencies ν1 = ν + Δν/2 and ν2 = ν − Δν/2. The frequency difference Δν was set to 50 kHz, and the average frequency ν was changed in steps of 10 kHz. The 17O NQR frequencies determined by these two techniques and the line widths are presented in Table 2. Other 1H−17O NQDR lines are either weak or hidden within much stronger 1H−14N NQDR lines and have not been observed. The OH distance ROH is calculated from the NQDR line widths as discussed in previous papers.23,24

Figure 6. 17O NQR frequencies ν5/2−3/2 and ν3/2−1/2 at the C−O−H and CO···H oxygen positions in dependence on the out-of-plane principal value qcc of the quadrupole coupling tensor. The full lines are calculated according to expression 6. The present data for the OH oxygen positions in AMP-BA (1), AMP-4HBA (2, 2′), and AMP-AA (3) are shown. The vertical line at qcc = 1 MHz separates the C−O−H and CO···H oxygen positions.

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DISCUSSION 1. 17O NQR. The 17O NQR data show that the carboxylic groups in anthranilic acid, 4-hydroxybenzoic acid, and benzoic acid form short hydrogen bonds with 2-amino-4,6-dimethylpyrimidine. The OH distance (∼0.11 nm) is much longer than in a noninteracting OH group, where it is equal to the sum of the hydrogen covalent radius (31 pm) and oxygen covalent radius (66 pm), that is, to 0.097 nm. Also, the quadrupole coupling constant is rather low. In previous studies,24,32 we have shown that the principal values of the 17O quadrupole coupling tensor at both the OH and the O···H oxygen positions correlate as

in Table 2 are shown in the same figure. The data for the OH positions in the carboxylic groups well agree with the correlation. The data for the hydroxyl group (ν5/2−3/2 calculated from ν5/2−1/2 and ν3/2−1/2) slightly deviate from the correlation. The value of qcc is the smallest and closest to the C−O−H → CO···H transition in the cocrystal 2-amino-4,6-dimethylpyrimidine− benzoic acid (1:1). This agrees with a slightly longer OH distance as compared to the other two compounds. The 17O NQR data may be related to the length of the O1− H···N1 hydrogen bond. This bond has the length d(O1− H···N1) = 0.2606 nm in AMP-BA,11,12 d(O1−H···N1) = 0.2711 nm in AMP-4HBA,13 and d(O1−H···N1) = 0.2701 nm in AMPAA.14 The length of the O−H(hydroxyl)···N3 hydrogen bond in AMP-4HBA is equal to 0.2742 nm. The lengths of the O1− H···N1 hydrogen bonds correlate well with the NQR data. In AMP-AA and AMP-4HBA, these lengths are approximately equal. Also, the 17O NQR frequencies at the O1 oxygen position do not differ much. In AMP-BA, the length of the O1−H···N1 hydrogen bond is significantly shorter, and also the 17O NQR frequencies are significantly shifted toward the transition C−O− H → CO···H that occurs at around qcc = 1 MHz. Significantly different 17O NQR data for the hydroxyl group and a shorter O− H distance are most probably the effect of different electron structures of the oxygen atoms in carboxyl and hydroxyl groups. The data for the hydrogen-bonded CO2 oxygen positions do not show a correlation at the first glance. The longest hydrogen bond (0.3003 nm) is observed in AMP-BA, whereas in AMP-4HBA this hydrogen bond is 0.2843 nm long. The 17O

qaa = −5.8 MHz − 0.37qcc qbb = 5.8 MHz − 0.63qcc

(6)

The principal axis denoted by “c” points perpendicular to either the C−O−H···A plane or the CO···H−D plane. Here, A and D denote the hydrogen-bond acceptor and donor, respectively. The principal axis denoted by “a” corresponds to the largest principal value (a = Z) for the C−O−H oxygen position, whereas the principal axis denoted by “b” corresponds to the largest principal value (b = Z) for the CO···H oxygen position. In symmetric C−O···H···OC hydrogen bonds, where hydrogen is shared 50:50 by the two oxygen atoms, the out-of-plane principal value qcc is experimentally observed around qcc = 1 MHz.33−35 In ref 35, we used by mistake the positive sign of the 17 O nuclear quadrupole moment and obtained the wrong sign of qcc. The value qcc ≈ 1 thus corresponds to the transition from the C−O−H hydrogen position to the CO···H hydrogen 6950



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NQR frequency ν3/2−1/2 is due to the stronger hydrogen bonding reduced from 1270 to 1250 kHz. In AMP-AA, where the CO2 oxygen atom is hydrogen bonded by two short NH2···O hydrogen bonds with the lengths 0.2830 and 0.2657 nm, we observe a larger NQR frequency: ν3/2−1/2 = 1290 kHz. As seen in Figure 6, ν3/2−1/2 exhibits a minimum at around qcc = −3 MHz. So the data for AMP-BA and AMP-4HBA are most probably at the left side of the minimum, whereas the data for AMP-AA seem to be at the right side of the minimum, closer to the CO···H → C−O−H transition. Unfortunately, we were not able to measure the intermediate 17O NQR frequency ν5/2−3/2 from these oxygen positions to confirm the above conclusion. 2. 14N NQR. In contrast to 17O, we have determined the complete set of 14N NQR frequencies in the investigated cocrystals and salts. There are three different nitrogen positions in AMP: amino and two ring nitrogen positions. In AMP-AA, there is in addition the amino nitrogen position in anthranilic acid. 2.1. 2-Amino-4,6-dimethylpyrimidine. In AMP, the two ring nitrogen positions only slightly differ in the NQR parameters. The average quadrupole coupling constant is at 77 K equal to 3.44 MHz, and the asymmetry parameter is at both positions equal to 0.188. At the amino nitrogen position, the quadrupole coupling constant is equal to 3.62 MHz, and the asymmetry parameter is higher, equal to 0.257. At room temperature, the average quadrupole coupling constant at the ring nitrogen positions is approximately 9 kHz larger than at 77 K, whereas the average asymmetry parameter is reduced to 0.166. At the amino nitrogen position, the quadrupole coupling constant is at room temperature approximately 35 kHz smaller than at 77 K, whereas the asymmetry parameter (η = 0.357) is larger than at 77 K. Such relatively small changes of the NQR parameters in the large temperature interval may be ascribed to molecular librations and small changes in hydrogen bonds produced by thermal expansion of crystals. 2.2. 2-Amino-4,6-dimethylpyrimidine−Anthranilic Acid, 2Amino-4,6-dimethylpyrimidine−4-Hydroxybenzoic Acid, and 2-Amino-4,6-dimethylpyrimidine−Benzoic Acid. In the cocrystals of AMP and weakest carboxylic acids AA (pKa = 4.95), 4HBA (pKa = 4.5), and BA (pKa = 4.2), we observe a significant decrease of the quadrupole coupling constants at the amino and ring nitrogen positions. In AMP-AA, the 14N quadrupole coupling constants at the amino nitrogen positions are equal to 3.43 and 3.07 MHz, whereas in the cocrystal formers they are equal to 3.6 MHz in AMP, and 3.6 and 3.7 MHz in polymorphs II and III of AA, respectively. In strongly hydrogen-bonded polymorph I of AA, the quadrupole coupling constant at the −NH2 nitrogen position is equal to 3.0 MHz, whereas at the −NH3+ nitrogen position it is equal to 1.6 MHz.31 As was observed also in amides,36 increasing strength of hydrogen bonds reduces the 14N quadrupole coupling constant at the −NH2 nitrogen position. According to the crystallographic data,14 the amino group of AA forms two hydrogen bonds with the distances d(H···O) = 0.183 nm and d(H···N) = 0.253 nm. These distances are slightly different from the distances published in ref 14. They are calculated under the assumption that the N−H distances are equal to 0.102 nm and not 0.094 and 0.089 nm as concluded from the X-ray measurements. The N−H and O−H distances, as measured by the X-ray diffraction, are usually too short. The origin of this is the low Z value (Z = 1) of the hydrogen nucleus, which produces only a weak diffraction of X-rays. The position of hydrogen atom is precisely measured by neutron diffraction, which is strong due

to nearly equal neutron and proton masses. The N−H distance 0.102 nm is taken as the sum of the covalent radius of hydrogen (31 pm) and the covalent radius of nitrogen (71 pm). In the further analysis, we assume that the N−H distances in a −NH2 group are both equal to 0.102 nm and calculate the H···A hydrogen-bond distances according to this value. The amino group of AMP also forms two hydrogen bonds with the distances d(H···O) = 0.182 nm and d(H···N) = 0.210 nm. The amino group of AMP thus forms stronger hydrogen bonds than the amino group of AA. We thus expect that the 14N quadrupole coupling constant at the amino nitrogen position of AMP is lower than that at the amino nitrogen position of AA. The 14 N quadrupole coupling constant at the ring nitrogen position N3 is close to the values observed in AMP, whereas at the nitrogen position N1, involved in an O−H···N hydrogen bond with the length d(O···N) = 0.2701 nm, the 14N quadrupole coupling constant is reduced for about 600 kHz. In AMP-4HBA, the 14N quadrupole coupling constant at the amino nitrogen position is equal to 3.47 MHz. The amino group forms two N−H···O hydrogen bonds with the H···O distances equal to 0.184 and 0.243 nm. These distances do not differ much from the distances observed at the amino nitrogen position of AA in AMP-AA, and also the 14N quadrupole coupling constants are nearly equal. At the ring nitrogen positions N1 and N3, the 14N quadrupole coupling constants are strongly reduced with respect to AMP (3.09 and 2.93 MHz versus 3.45 MHz). The two nitrogen atoms are involved in two hydrogen bonds with the lengths d(O1···N1) = 0.2711 nm and d(O(hydroxyl)···N3) = 0.2742 nm. These distances are longer than the O1−H···N1 distance in AMP-AA, and the quadrupole coupling constants are therefore larger. The lower 14N quadrupole coupling constant in AMP-4HBA may be assigned to the nitrogen position N1 that is involved in a shorter O−H···N hydrogen bond than the nitrogen position N3. The 14N quadrupole coupling constant at the amino nitrogen position in AMP-BA is equal to 3.26 MHz. The amino group forms in this substance two hydrogen bonds with the lengths d(H···O) = 0.200 nm and d(H···N) = 0.209 nm. These values are recalculated from the data given in ref 12. At the ring nitrogen position N3, the 14N quadrupole coupling constant is nearly the same as in AMP (3.45 MHz), whereas at the ring nitrogen position N1, the 14N quadrupole coupling constant is strongly reduced, and is equal to 2.60 MHz. The length of the hydrogen bond O−H···N formed by the nitrogen atom N1 is equal to 0.2606 nm. This distance is shorter than the corresponding distances in AMP-AA and AMP-4HBA, and the 14N quadrupole coupling constant is correspondingly smaller 2.3. 2-Amino-4,6-dimethylpyrimidine−5-Chlorosalicylic Acid, 2-Amino-4,6-dimethylpyrimidine−Malonic Acid, and 2-Amino-4,6-dimethylpyrimidine−Oxalic Acid. In the salts of AMP and stronger carboxylic acid 5CSA (pKa = 2.8), MA (pKa = 2.6), and OA (pKa = 1.25), proton transfer occurs according to the crystallographic data. The proton transfer has a strong impact on the 14N NQR frequencies at the N1H+ nitrogen positions. In AMP-5CSA. we observe within the experimental resolution a single amino and two ring nitrogen positions. According to the crystal structure, there are two independent AMPH+ ions in the unit cell. The two ions look almost identical with one another having similar molecular interactions. They differ from each other with slight variations in the bond distances, bond angles, and hydrogen-bond lengths.7 The difference of the NQR frequencies in the two ions seems to be smaller than the resolution of NQDR (5 kHz), and we in fact observe the average 6951



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NQR frequencies of the two ions. The 14N quadrupole coupling constant at the amino nitrogen position is rather low, equal to 2.677 MHz. This is consistent with the short hydrogen bond formed by the nitrogen atom. It forms two N2−H···O2 hydrogen bonds with the H···O distances equal 0.183 and 0.179 nm for one ion and 0.187 and 0.177 nm for the other ion. These distances are shorter than the corresponding distances at the amino nitrogen position of AMP in AMP-AA, and the 14N quadrupole coupling constant is consequently smaller. At the ring nitrogen position N3, the average quadrupole coupling constant (3.53 MHz) is slightly larger than in AMP, whereas at the ring nitrogen position N1 it is much smaller, equal to 1.77 MHz. This large reduction of the 14N quadrupole coupling constant is the result of the proton transfer from O1 to N1. At the amino nitrogen position in AMP-MA, we again observe a rather low 14N quadrupole coupling constant, equal to 2.760 MHz. This value is about 0.1 MHz larger than in AMP-5CSA. This is consistent with slightly longer hydrogen bonds formed by the N2 atom: d(H···O) = 0.176 nm, d(H···N) = 0.198 nm. The 14 N quadrupole coupling constant at the N3 nitrogen position is nearly equal to that in AMP, whereas at the N1H+ nitrogen position it is smaller than in AMP-5CSA, equal to 1.730 MHz. The crystal structure of AMP-OA is to our knowledge not yet known. According to the NQR data, we can draw the following conclusions on hydrogen bonding in this substance. AMP-OA is definitely a salt. The 14N quadrupole coupling constant of nitrogen N1 is equal to 1.573 MHz, which is even less than in AMP-5CSA and AMP-MA. The 14N quadrupole coupling constant at the nitrogen position N3 (3.54 MHz) is approximately equal to that in AMP-5CSA, so the nitrogen atom at this positions forms hydrogen bonds of similar strengths to those in AMP-5CSA. The amino nitrogen atom exhibits a slightly larger 14N quadrupole coupling constant as compared to that in AMP-MA, which slightly exceeds the 14N quadrupole coupling constant in AMP-5CSA. In both salts, the amino nitrogen atom forms two moderate hydrogen bonds with the average H···A bond length equal to 0.182 nm in AMP-5CSA and 0.187 nm in AMP-MA. So the amino group in AMP-OA seems to form two moderate hydrogen bonds of approximately the same length as in AMP-MA with an average H···A distance equal to approximately 0.19 nm. 2.4. Correlation of 14N NQR and Structural Parameters. 2.4.1. Amino Group. Long ago, Soda and Chiba37 observed a linear correlation between the deuteron quadrupole coupling constant and inverse third power of the 2H···O distance in O−2H···O hydrogen bonds. We propose a similar correlation for 14 N quadrupole coupling constant at the amino (C−NH2) nitrogen position. As the hydrogen-bond donor, an amino group may form two N−H···A hydrogen bonds. We suppose that the contributions of the two hydrogen bonds (N−H1···A1 and N− H2···A2) to the quadrupole coupling constant sum as

Figure 7. Correlation of 14N quadrupole coupling constant e2qQ/h = |qZZ| and the sum of the inverse third powers of the hydrogen-bond distances d(H1···A1) and d(H2···A2). Full symbols represent the cases where A1 = N and A2 = O, whereas open symbols represent the cases where A1 and A2 are both oxygen atoms.

The principal values of the 14N quadrupole coupling tensor at a given nitrogen positions are often intercorrelated.8,19,38 These correlations are helpful in the experimental search for the 14N NQR frequencies and in the assignment of a quadrupole coupling tensor to a particular nitrogen position. The correlations reflect the strength of inter- and intramolecular interactions and molecular substitutions. It is thus interesting to check whether the present data show some correlations and to link these correlations to crystal structure and hydrogen bonding. First, we check the correlation of the principal values of the 14N quadrupole coupling tensor at the C−NH2 nitrogen position. The 14N quadrupole coupling tensor of a noninteracting amino group can be determined by microwave spectroscopy in the gas phase. In contrast to NQR, the microwave spectroscopy gives also the sign of the quadrupole coupling constant. The measurements have been performed in aniline, p-toluidine, and 3-aminophenol.39,40 The experimental results show that the principal axis Z of the quadrupole coupling tensor is perpendicular to the C−NH2 plane and the principal value qZZ is equal to −4.20 MHz. The two in-plane principal axes of the quadrupole coupling tensor are presented in Figure 8. The two

Figure 8. In-plane principal axes of the quadrupole coupling tensor at the pyrimidine ring nitrogen position (i) and at the amine nitrogen position (ii). The third principal axis c points perpendicular to the plane in both cases.

smaller principal values of the quadrupole coupling tensor are qaa = qYY = 2.37 MHz and qbb = qXX = 1.83 MHz. We assume that also in the solid phase the quadrupole coupling constant is negative and the principal axis Z is normal to the C−NH2 plane. The correlation of the principal values of the quadrupole coupling tensor at the amino nitrogen position is presented in Figure 9. In addition to the present data and the data obtained by microwave spectroscopy in aniline and p-toluidine, we added the data obtained in 2-aminopyrimidine,30 anthranilic acid,31 and sulfa drugs sulfanilamide, sulfadiazine, sulfamerazine, sulfamethazine, and sulfathiazole.41 In case of sulfa drugs, we only included the NQR data from the substances where the amino group was

e 2qQ /h = |qZZ | = P + Q (d(H1···A1)−3 + d(H2···A2)−3 ) (7)

The experimental data obtained in the present study are presented in Figure 7. A monotonous dependence of e2qQ/h on d(H1···A1)−3 + d(H2···A2)−3 is indeed observed. The parameters P and Q obtained after fitting the experimental data to expression 7 are P = 5.0 MHz and Q = −7.1 kHz nm3. For AMP-OA with unknown crystal structure, the sum d(H1···A1)−3 + d(H2···A2)−3 is according to expression 7 equal to 310 nm−3. 6952



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Here, q0 is the quadrupole coupling tensor of a noninteracting amino group, and (δq)LP is the change of the quadrupole coupling tensor produced by the deformation of the nitrogen lone pair electron orbital, which is directed along the c axis. The changes (δq)H1 and (δq)H2 directed along the N−H1 and N−H2 σ bonds are produced by hydrogen bonding. For the sake of simplicity, we assume that the C−N−H and H−N−H angles are equal to 120°. A linear correlation, as observed in Figure 9, is obtained when the off-diagonal element qab = (xH1 − xH2)3√3/8 may be neglected and when the lone pair contribution xLP is proportional to xH1 + xH2. The off-diagonal matrix element qab is small when the two hydrogen bonds do not differ much in strength (xH1 ≈ xH2). It also does not change the principal values of q in the first-order perturbation theory, so we neglect it. Expression 8 is obtained when xLP = −0.46(xH1 + xH2). A reduction of the quadrupole coupling constant, which is observed in case of hydrogen bonding, occurs when xLP > 0 and consequently xH1 + xH2 < 0. The negative values of xH1 and xH2 show that under the influence of hydrogen bonding, the electron charge density at the nitrogen position in a N−H σ bond increases. The variation of the principal values of the 14N quadrupole coupling tensor can be in case of N−H···A hydrogen bonding described by a single parameter x, x = xLP − (xH1 + xH2)/ 2 = −0.96(xH1 + xH2) = 2.1xLP, as follows:

Figure 9. Correlation of principal values of the 14N quadrupole coupling tensor at the amino nitrogen positions. The data for the gas phase are on the right side of the diagram. The data for the strongest hydrogen bonds are on the left side of the diagram.

clearly assigned. A nearly linear correlation is observed, which may be expressed as qYY = 1.91 MHz − 0.11qZZ qXX = −1.91 MHz − 0.89qZZ

(8)

To get a deeper insight into the effect of hydrogen bonding on the electron charge distribution at the nitrogen atom, we use a simple model based on the Townes and Dailey theory,42 where we express the 14N quadrupole coupling tensor q in the a, b, c coordinate system as q = q 0 + (δ q)LP + (δ q)H1 + (δ q)H2

qcc = −4.20 MHz + x qbb = 1.83 MHz − 0.89x

(9)

qaa = 2.37 MHz − 0.11x

The four terms are written in matrix form as

In the presently studied substances, the maximum value of x, x ≈ 1.5 MHz, is reached in AMP-5CSA. 2.4.2. Pyrimidine Ring. Approximate principal directions of the quadrupole coupling tensor at the pyrimidine ring nitrogen position are shown in Figure 8. Microwave spectroscopic data43,44 show that the largest principal value qZZ of the 14N quadrupole coupling tensor in the gas phase is negative, qZZ = −4.78 MHz, and the principal axis Z is directed along the lone pair orbital (Z = a). The principal value qYY is equal to 3.35 MHz, and the principal axis Y is normal to the plane of the pyrimidine ring (Y = c). The principal value qXX = qbb is equal to 1.43 MHz. We assume that also in the solid phase qZZ is negative and plot the correlation diagram of qXX and qYY versus qZZ for various substituted pyrimidines (ref 25) and the presently studied cocrystals and salts of 2-amino-4,6-dimethylpyrimidine. The correlation diagram is presented in Figure 10. The correlation diagram is not simple, as in case of the amino group, and the ring

⎛ 2.37 0 ⎞ 0 ⎜ ⎟ q 0 = ⎜0 1.83 0 ⎟⎟ MHz ⎜ ⎝0 −4.20 ⎠ 0 ⎛ 1 ⎞ 0 0⎟ ⎜− ⎜ 2 ⎟ (δ q)LP = x LP⎜ 1 ⎟ − 0 ⎜0 2 ⎟⎟ ⎜ ⎝0 0 1⎠

(δ q)H1

⎛ 1 ⎜− ⎜ 8 ⎜ = x H1⎜ 3 3 ⎜ 8 ⎜ ⎜0 ⎝

(δ q)H2 ⎛ 1 ⎜− ⎜ 8 ⎜ = x H2⎜− 3 3 8 ⎜ ⎜ ⎜0 ⎝

−

3 3 8

0

5 8

0

0

−

3 3 8

0

5 8

0

0

−

⎞ ⎟ ⎟ ⎟ ⎟ ⎟ ⎟ ⎟ ⎠

1 2

1 2

⎞ ⎟ ⎟ ⎟ ⎟ ⎟ ⎟ ⎟ ⎠

(11)

Figure 10. Correlation of the principal values qYY and qXX of the 14N quadrupole coupling tensor versus the largest principal value qZZ in substituted pyrimidine (■) and in 2-amino-4,6-dimethylpyrimidine cocrystals and salts (□).

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Table 3. Principal Values qZZ and qYY of the 14N Quadrupole Coupling Tensor and the Parameters xπ and xLP Describing the Population of the π Electron Orbital and Deformation of the Lone Pair Electron Orbital in Several Substituted and Hydrogen-Bonded Pyrimidines

substitution seems to have a different effect on the quadrupole coupling tensor as the hydrogen bonding. To understand the correlation diagram, we analyze the quadrupole coupling tensor in a simple model where we assume that the hydrogen bonding and the substitution of hydrogen atoms attached to the ring by different atoms or functional groups deform the lone pair electron orbital and change the population of the π electron orbital at the nitrogen position. The quadrupole coupling tensor q can be in this case written as q = q 0 + (δ q)LP + (δ q)π

substance pyrimidinea,b 2-methylpyrimidine·1/2H2Oa,b 4-methylpyrimidinea

(12)

14

5-methylpyrimidinea,b 4,6-dimethylpyrimidinea,b 2-chloropyrimidinea,b 4,6-dichloro-2-methylpyrimidinea 2,4-dimethoxy-5methylpyrimidinea

Here, q0 is the N quadrupole coupling tensor at the pyrimidine ring nitrogen position in the gas phase, and the parameters xLP and xπ measure the deformation of the lone pair electron orbital and the population of the π electron orbital, respectively. The three contributions to the quadrupole coupling tensor are in the coordinate system a, b, c written as follows: ⎛−4.78 0 0 ⎞ ⎜ ⎟ q0 = ⎜ 0 1.43 0 ⎟ MHz ⎜ ⎟ ⎝0 0 3.35⎠

(δq)LP

⎛1 0 0 ⎞ ⎜ ⎟ ⎜0 − 1 0 ⎟ = x LP⎜ ⎟ 2 ⎜ 1⎟ ⎜0 0 − ⎟ ⎝ 2⎠

2-aminopyrimidinea,b 2-amino-4,6-dimethylpyrimidine (AMP)a,b AMP-AA

⎛ 1 ⎞ 0 0⎟ ⎜− ⎜ 2 ⎟ (δq)π = xπ ⎜ 1 ⎟ − 0 ⎜0 2 ⎟⎟ ⎜ ⎝0 0 1⎠

AMP-4HBA AMP-BA AMP-5CSAb

(13)

AMP-MA

The parameters xLP and xπ are for various substituted pyrimidines and cocrystals and salts of 2-amino-4,6-dimethylpyrimidine presented in Table 3. The deformation of the lone pair electron orbital with respect to the gas phase (xLP) is weak (∼200 kHz) in methyl- and chlorosubstituted pyrimidine. In 2,4-dimethoxy-5-methylpyrimidine, it is larger (440 and 720 kHz), which may be the effect of interaction of methoxy groups and the pyrimidine ring nitrogen atoms. The crystal structure of this compound, which may explain this exception, has to our knowledge not yet been measured. In 2-aminopyrimidine, 2-amino-4,6-dimethylpyrimidine, and the cocrystals and salts of 2-amino-4,6-dimethylpyrimidine, the nitrogen lone pair orbital is more affected. At the moderately hydrogen-bonded position (N3), it is typically 900 kHz, whereas at the strongly hydrogen-bonded position (N1), it ranges from 1670 kHz in AMP-AA to 2010 kHz in AMP-BA. In the salts, xLP ranges from 2690 kHz in AMP-5CSA to 2950 kHz in AMP-OA. The transition from cocrystal to salt (proton transfer) occurs at a value of xLP somewhere between 2010 and 2690 kHz. The change of the population of the π electron orbital with respect to pyrimidine is mainly affected by the ring substitution. The methyl group has a weak effect on xπ. The substitution of hydrogen by chlorine changes xπ by about −500 kHz (the population of the π electron orbital increases). The substitution of hydrogen by a methoxy group seems to have a similar effect. In amino-substituted pyrimidine, there is no systematic variation of xπ. It is equal to about 600 kHz independent of hydrogen bonding. The above conclusions explain the correlation diagram presented in Figure 10. In case of substituted pyrimidine, the quadrupole coupling tensor varies mainly as the consequence of the varying population of the π electron orbital, which produces a

AMP-OA a

qZZ (kHz)

qYY (kHz)

xπ (kHz)

xLP (kHz)

−4436 −4396 −4398 −4277 −4443 −4225 −4348 −4194 −3824

3074 2914 2992 2834 3104 2754 2657 2384 2093

−140 −330 −220 −350 −100 −420 −640 −900 −1040

270 220 270 330 280 345 110 140 440

−3649 −3733 −3438

2165 1957 2043

−830 −1160 −850

720 470 920

−3461 −2850 −3087 −2930 −3453 −2599 −3527 −1770 −3451 −1730 −3539 −1573

2058 1996 2024 2034 2076 1996 2178 1370 2206 1310 2214 1366

−840 −520 −640 −520 −810 −350 −730 −630 −640 −690 −690 −510

900 1670 1370 1590 920 2010 890 2690 1010 2710 900 2950

Reference 30. bAverage values.

varying axially symmetric contribution to the quadrupole coupling tensor directed along the principal axis Y. In hydrogen-bonded 2-amino-4,6-dimethylpyrimidine cocrystals and its salts, the population of the π electron orbital is more or less constant, and the hydrogen bonding affects the lone pair electron orbital. This produces a variable axially symmetric contribution to the quadrupole coupling tensor directed along the principal axis Z.

■

CONCLUSIONS N and 17O NQR frequencies have been measured in 1:1 cocrystals of 2-amino-4,6-dimethylpyrimidine and anthranilic acid, 4-hydroxybenzoic acid, and benzoic acid and in salts of 2amino-4,6-dimethylpyrimidine and 5-chlorosalicylic acid, malonic acid, and oxalic acid. The 17O NQR frequencies measured in cocrystals at the O− H···N oxygen position indicate short hydrogen bonds. A systematic decrease of the 17O quadrupole coupling constant on increasing strength of the hydrogen bond is observed. The O−H distances deduced from the line widths of the 17O NQR lines show that the hydrogen atom is in the hydrogen bonds formed by the carboxylic groups for about 0.01 nm displaced from the oxygen atom toward the center of the hydrogen bond. In the O−H···N hydrogen bond formed by the hydroxyl group, which is only slightly longer than the O−H···N hydrogen bonds formed by the carboxyl group, the hydrogen atom remains close to the oxygen atom. 14

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A large variation of the 14N quadrupole coupling constant at the amino nitrogen position is observed in the studied compounds. The variation is related to the strengths of the two N−H···A hydrogen bonds formed by the nitrogen atom. Increasing strengths of the two hydrogen bonds reduce the 14N quadrupole coupling constant. A linear relation between the 14N quadrupole coupling constant and the sum of the inverse third powers of the H···A distances is deduced. This relation, which is analogous to the well-known Soda and Chiba relation for deuteron,29 may be used to estimate an average H···A distance by NQR. A linear correlation of the principal values of the 14N quadrupole coupling tensor is observed in the solid phase. This correlation extends also to the gas phase. The correlation is analyzed in a simple model based on the Townes and Dailey theory.35 The model shows that a hydrogen bond produces a displacement of the electron charge in the N−H σ bond toward nitrogen. The deformation of the nitrogen lone pair electron orbital is proportional to this displacement. The measurement of the 14N quadrupole coupling constant can be used to determine an average strength of the two hydrogen bonds formed by the amino group. At the ring nitrogen position, hydrogen bonding and proton transfer produce a large decrease of the 14N quadrupole coupling constant. An increasing strength of the N···H−O hydrogen bond reduces the 14N quadrupole coupling constant. A linear correlation of the principal values of the 14N quadrupole coupling tensor is observed in cocrystals and salts of 2-amino4,6-dimethylpyrimidine. This correlation differs from the correlation observed in substituted pyrimidine, where the hydrogen atoms are replaced by other atoms or functional groups. The correlation is analyzed in a model in which it is assumed that the hydrogen bonding and substituents deform the nitrogen lone pair electron orbital and change the population of the nitrogen π electron orbital. The analysis shows that the two changes are nearly independent. The population of the nitrogen π electron orbital is nearly the same in the studied cocrystals and salts independent of the strength of the hydrogen bond and even proton transfer. The variation of the population of the π electron orbital has on the other hand nearly no effect on the lone pair electron orbital. The 14N NQR data for 2-amino-4,6-dimethylpyrimidine− oxalic acid show that proton transfer O−H···N → O−···H−N occurred, so it is a salt. The 14N quadrupole coupling constant of nitrogen N3 is rather high, so it is only weakly hydrogen bonded. The 14N quadrupole coupling constant of the amino nitrogen suggests that the amino group is bound by two N−H···A hydrogen bonds with an average H···A distance equal to 0.19 nm. The obtained results show that NQR is a useful technique for the study of details of the crystal structure, especially hydrogen bonding, and electron charge distribution around the quadrupole nucleus.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Vishweshwar, P.; McMahon, J. A.; Bis, J. A; Zaworotko, M. J. Pharmaceutical Co- crystals. J. Pharm. Sci. 2006, 95, 499−516. 6955



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Hydrogen Bonds in Cocrystals and Salts of 2-Amino-4,6

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