Nuclear Quadrupole Resonance Investigation of Hydrogen Bonding in

Article pubs.acs.org/JPCB

Nuclear Quadrupole Resonance Investigation of Hydrogen Bonding in Some Cocrystals of 2,3,5,6-Tetramethylpyrazine and Carboxylic Acids 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

‡

ABSTRACT: Cocrystals of 2,3,5,6-tetramethylpyrazine and several carboxylic acids have been prepared, and the complete 14N nuclear quadrupole resonance spectra have been measured. The 14 N nuclear quadrupole resonance spectra have been used to check whether the cocrystals are indeed formed and to investigate the hydrogen bonding scheme of 2,3,5,6-tetramethylpyrazine molecules. Since a 2,3,5,6-tetramethylpyrazine molecule has two hydrogen bond acceptors, it may form either 1:1 or 1:2 cocrystals with carbocylic acids. 14N nuclear quadrupole resonance is used to distinguish between these two possibilities. Rather large 14N quadrupole coupling constants in the investigated cocrystals show that in these systems proton transfer O−H···N → O−···H−N+ does not occur. The quadrupole coupling tensor in 2,3,5,6-tetramethylpyrazine cocrystals has been analyzed in terms of the deformation of the electron lone pair orbital and population of the π-electron orbital. The analysis shows that the two effects are correlated.

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INTRODUCTION Crystalline materials with desired physical, chemical, or pharmaceutical properties can be obtained by the formation of cocrystals and crystal polymorphs.1−6 Cocrystals are the crystalline structures formed by two or more components bound by non-covalent bonds. They are constructed through several types of interaction, including hydrogen bonding, π−π stacking, and van der Waals forces. The properties of a cocrystal usually differ from the properties of the cocrystal formers. In a cocrystal, homosynthons and heterosynthons generally occur. Their occurrence depends on the molecular architecture and the positions and properties of functional groups. Several cocrystals and crystals may exist in more than one crystal structure. These polymorphic forms of a given substance in general differ in macroscopic properties. Various polymorphs can be obtained by changing the conditions (solvent, temperature, pressure, ...) during the crystallization. 2,3,5,6-Tetramethylpyrazine (TMP), also known as ligustrazine (Figure 1), is a pharmacologically active amide alkaloid. In

ligustrazine may become a novel drug candidate for the treatment of Alzheimer disease.9 TMP is also used as a food additive for its chocolate-like taste and fragrance. This compound exhibits rapid first-pass metabolism, a short biological half-life, low stability, and potential vascular irritation that restrict its use for long-term therapy.8 The application of cocrystals of TMP may therefore have some advantages with respect to the application of pure TMP. In addition, the formation of cocrystals is also interesting from the point of view of the electronic structure of the TMP molecule. The cocrystals of TMP have not been widely studied so far. For cocrystals TMP−chloranilic acid (1:1),10 TMP−squaric acid (1:1),11 and TMP−picrinic acid (1:2),12 the crystal structures have been determined and the influence of the cocrystal formation on the methyl group reorientation has been investigated. Hydrogen bonds in TMP−chloranilic acid (1:1) have been investigated by 14N and 35Cl nuclear quadrupole resonance.13 Supramolecular synthon polymorphism has been observed in cocrystals of TMP and 4-hydroxybenzoic acid (1:2).14 The compound may crystallize in a metastable antihierarchic form I, where the molecules form chains in the following way. The hydroxyl groups of two 4-hydroxybenzoic acid molecules are hydrogen-bonded to a TMP molecule, and the carboxyl groups of two 4-hydroxybenzoic acid molecules in between two TMP molecules are bound by a pair of O−H···O hydrogen bonds. In the stable hierarchic form II, the carboxyl groups of two 4hydroxybenzoic acid molecules are hydrogen-bonded to a TMP

Figure 1. 2,3,5,6-Tetramethylpyrazine (TMP).

Chinese medicine, ligustrazine has traditionally been used to treat various cardiovascular and neurovascular complications.7,8 Recent animal studies have proved that ligustrazine can significantly improve the hippocampal cholinergic system function, attenuate oxidative damage, and therefore remarkably enhance the learning and memory abilities, suggesting that © 2014 American Chemical Society

Received: December 17, 2013 Revised: January 9, 2014 Published: January 9, 2014 996

dx.doi.org/10.1021/jp412332p | J. Phys. Chem. B 2014, 118, 996−1002

The Journal of Physical Chemistry B

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molecule. Two 4-hydroxybenzoic acid molecules are bound together by the O−H···O hydrogen bond between the hydroxyl group and the carbonyl oxygen of the carboxyl group. Cocrystals of 4-hydroxybenzoic acid and 2,3,5,6-tetramethylpyrazine (2:1) exhibit the first supramolecular synthon polymorphism in a cocrystal; metastable antihierarchic polymorph I converts to stable hierarchic form II. Nuclear quadrupole resonance (NQR) proved to be a sensitive indicator of the electron charge distribution in the part of the molecule where the quadrupole atomic nucleus is located.15 Nitrogen atoms are of particular importance in numerous organic and biologically important compounds where they form functional groups acting either as hydrogen bond donors or as hydrogen bond acceptors. The nucleus of the most abundant nitrogen isotope 14N has a nonzero electric quadrupole moment and is thus suitable for NQR. The 14N NQR frequencies depend on the population of the nitrogen electron orbitals and represent a sensitive tool for the study of hydrogen bond strength and the position of protons within the hydrogen bond.16 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.17,18 Sharp 14N NQR lines observed at the frequencies different than in the cocrystal formers prove that the cocrystal is indeed formed. The complete set of the 14N NQR frequencies uniquely characterizes a cocrystal. When crystal polymorphs are formed, they differ in the 14N NQR spectra. In a previous study,16 we have investigated cocrystals and salts of 2-amino-4,6-dimethylpyrimidine (AMP) and carboxylic acids by 14N NQR. We observed strong variation of 14N NQR parameters related to various strengths of O−H···N hydrogen bonds and even proton transfer (O−H···N → O−···H−N+). The variation of the 14N NQR parameters is related to the deformation of the nitrogen lone pair orbital and the electron population of σ and π bonds formed by the nitrogen atom. In the present study, we prepared cocrystals TMP−acetic acid (1:2), TMP−anthranilic acid (1:1), TMP−benzoic acid (1:1), TMP−citric acid (1:1), TMP−5-chlorosalycilic acid (1:1), TMP−4-hydroxybenzoic acid (1:2), TMP−oxalic acid (1:1), TMP−malonic acid (1:1), and TMP−fumaric acid (1:1). The structural formulas of the carboxylic acids used are shown in Figure 2. 14N NQR is used to characterize the cocrystals and to investigate hydrogen bonds and possible proton transfer in these systems. 14 N NQR. The nucleus of the nitrogen isotope 14N has in its ground state a spin of I = 1 and a nonzero electric quadrupole moment. The interaction of the nuclear electric quadrupole moment eQ with the electric field gradient (EFG) tensor Vik, Vik = ∂2V/∂xi∂xk, at the position of the atomic nucleus, results in three generally nonequidistant nuclear quadrupole energy levels and three resonance (NQR) frequencies ν+ ≥ ν− ≥ ν0 equal to19 ν+ =

e 2qQ (3 + η) 4h

ν− =

e 2qQ (3 − η) 4h

ν0 = ν+ − ν− =

e 2qQ η 2h

Figure 2. Structural formulas of carboxylic acids used in the present study.

Here, e2qQ/h is the quadrupole coupling constant and η is the asymmetry parameter of the EFG tensor. They are related to the principal values VXX, VYY, and VZZ of the EFG tensor (|VZZ| ≥ |VYY| ≥ |VXX|) as e2qQ/h = |eQVZZ|/h and η = (VXX − VYY)/ VZZ. The quadrupole coupling tensor q ik , which can be determined by NQR or NMR, is equal to the product of the EFG tensor and the nuclear quadrupole moment eQ divided by the Planck constant h, qik = eQVik/h. It is expressed in frequency units. The present knowledge of nuclear electric quadrupole moments20 allows us to calculate the EFG tensor from the quadrupole coupling tensor. The sign of the largest principal value qZZ of the quadrupole coupling tensor can in general not be determined by NQR or NMR, so only the relative signs of the elements of the quadrupole coupling tensor with respect to qZZ can be determined by these techniques. Different experimental techniques, as for example microwave spectroscopy, or quantum chemical calculations are needed to determine its sign. The absolute value of the largest principal value of the 14N quadrupole coupling tensor and the asymmetry parameter η are calculated from the 14N NQR frequencies as | qZZ| = e2qQ/h = 2(ν+ + ν−)/3 and η = 2ν0/|qZZ|. The two smaller principal values of the quadrupole coupling tensor are related to qZZ and η as qYY = −qZZ(1 + η)/2 and qXX = −qZZ(1 − η)/2.

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EXPERIMENTAL SECTION The samples of TMP, acetic acid (AcA), anthranilic acid (AnA), benzoic acid (BA), citric acid (CA), 5-chlorosalycilic acid (5CSA), 4-hydroxybenzoic acid (4HBA), oxalic acid (OA), malonic acid (MA), and fumaric acid (FA) were purchased at Sigma-Aldrich and used as obtained. The cocrystals were obtained by mixing hot methanol solutions of cocrystal formers. The solutions were then left at room temperature for a few days until the cocrystals grew from the solution. In order to obtain the cocrystal TMP−4HBA (1:2) in the polymorphic form I, we dissolved the cocrystal formers in 1:2 molar ratio in acetone and left the solution at room temperature to slowly evaporate until the cocrystals formed.

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The 14N NQR frequencies have been measured by 1H−14N nuclear quadrupole double resonance (NQDR). In the present study, we have used the solid-effect technique21 and the technique using multiple frequency sweeps and two-frequency irradiation.22,23 These techniques are based on magnetic field cycling. The details of the present experimental setup and the measuring procedure were published in a previous paper.24

where two AcA molecules are bound to a TMP molecule and there is a symmetry element (inversion center, mirror plane, or 2-fold axis) present in the unit cell that makes the two nitrogen positions in a TMP molecule equivalent. The rest of the sample, not used in the NQDR measurement, exhibited a strong smell of acetic acid, which disappeared after about 1 week. Then, we measured the 14N NQR frequencies in this part of the sample and they are equal as in TMP. The AcA molecules evaporated from the sample, and the TMP−AcA cocrystals transformed to TMP crystals. TMP−Benzoic Acid, TMP−5-Chlorosalycilic Acid, and TMP−Anthranilic Acid. The three polycrystalline cocrystal samples were prepared by dissolving the cocrystal formers in 1:1 molar ratio in methanol. The cocrystals grew after a few days. The 1H−14N NQDR spectrum of TMP−BA (1:1) at T = 210 K is shown in Figure 3b. We clearly observe two sets of 14N NQR frequencies: (4025 kHz, 2984 kHz, 1041 kHz) and (3495 kHz, 2670 kHz, 825 kHz). The measurements were performed at a temperature lower than room temperature due to experimental reasons. The proton spin−lattice relaxation time T1 at the Larmor frequency lower than 1 MHz is at room temperature too short for our experimental setup to be used. By cooling the sample to 210 K, T1 in this frequency region increases and becomes long enough (T1 > 0.3 s) to perform the measurements. The number of nitrogen positions is consistent with the expected hydrogen bonding scheme of the 1:1 cocrystal where all TMP molecules are equivalent. The 14N NQR frequencies in the first set are slightly higher than in TMP. This set may be assigned to the non-hydrogen-bonded nitrogen position. The 14N NQR frequencies in the second set are significantly lower than in TMP. They correspond to the hydrogen-bonded nitrogen position. In TMP−5CSA (1:1), we observe at T = 170 K two sets of 14 N NQR frequencies: (4117 kHz, 3010 kHz, 1107 kHz) from the non-hydrogen-bonded nitrogen position and (3335 kHz, 2558 kHz, 777 kHz) from the hydrogen-bonded nitrogen position. In TMP−AnA, we observe at 180 K three sets of 14N NQR frequencies: (3894 kHz, 2897 kHz, 997 kHz), (3348 kHz, 2623 kHz, 761 kHz), and (2982 kHz, 2312 kHz, 670 kHz). The first set may be assigned to the non-hydrogen-bonded or perhaps weakly hydrogen-bonded nitrogen position in the TMP ring. The third set of frequencies is comparable to the sets experimentally observed in the C−NH2 groups.16 In addition, we observed strong solid effect deeps around these 14N NQR frequencies, so the third set of 14N NQR frequencies may be assigned to the nitrogen position where 14N and 1H strongly interact, i.e., to the −NH2 nitrogen position in anthranilic acid. The second set of 14N NQR frequencies thus corresponds to the hydrogen-bonded nitrogen position in the TMP ring. TMP−4-Hydroxybenzoic Acid (1:2). We prepared cocrystals several times from the methanol and from the acetone solutions. In all cases, we observed a single set of 14N NQR frequencies: (3426 kHz, 2627 kHz, 799 kHz). This means that we obtained a single polymorph independent of the solvent. A single set of 14N NQR frequencies is consistent with the hydrogen bonding scheme in the 1:2 cocrystal with two equivalent nitrogen positions in a TMP molecule. Rather large shifts of the 14N NQR frequencies with respect to TMP show that the hydrogen bonding is strong, so the carboxyl groups and not the hydroxyl groups of two 4HBA molecules interact with a TMP molecule. To check the stability of cocrystal, we repeated

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EXPERIMENTAL RESULTS The 14N NQR frequencies in TMP have been first measured at room temperature (295 K) by NQDR. The 1H−14N NQDR spectrum obtained by multiple frequency sweeps of the rf magnetic field and Larmor frequency scan (low-frequency part, ν0) and two frequency irradiation at νH = ν0 (high-frequency part, ν+, ν−) is presented in Figure 3a.

Figure 3. 1H−14N NQDR spectra of 2,3,5,6-tetramethylpyrazine at T = 295 K (a) and 2,3,5,6-tetramethylpyrazine−benzoic acid (1:1) at T = 210 K (b). The labels 1 and 2 denote the hydrogen-bonded nitrogen position and non-hydrogen-bonded nitrogen position, respectively.

We observe one set (ν+, ν−, ν0) of 14N NQR frequencies (3975 kHz, 2945 kHz, 1030 kHz), so all nitrogen positions in the crystal structure are equivalent. The quadrupole coupling constant e2qQ/h and the asymmetry parameter η are equal to 4613 kHz and 0.447, respectively. Our results may be compared to the results of a previous measurement of 14N NQR frequencies in TMP at T = 77 K which gave e2qQ/h = 4762 kHz and η = 0.450.25 The quadrupole coupling constant is at room temperature slightly smaller than at 77 K, which may be the result of molecular librations which partially average the quadrupole coupling tensor. The molecular librations are at a higher temperature more intensive than at a lower temperature, so at a higher temperature the quadrupole coupling constant is averaged to a lower value than at a lower temperature. TMP−Acetic Acid. We attempted to produce the 1:1 cocrystal TMP−AcA by dissolving the cocrystal formers in 1:1 molar ratio in methanol. After a few days, we collected the crystals from the solution and measured the 14N NQR frequencies. We observed at room temperature a single set of 14 N NQR frequencies: (3703 kHz, 2791 kHz, 912 kHz). The NQDR lines are narrow and the 14N NQR frequencies are significantly lower than in TMP, so the cocrystal is formed. The presence of a single nitrogen position is not consistent with the 1:1 cocrystal. In a TMP molecule, there are two nitrogen positions, whereas an AcA molecule has a single carboxylic group, so it may form the O−H···N hydrogen bond to a single nitrogen atom. We therefore expect to observe two nitrogen positions: one with the NQR frequencies close to the ones observed in TMP (non-hydrogen-bonded nitrogen position) and the other with different 14N NQR frequencies (hydrogenbonded nitrogen position). The fact that we observe a single nitrogen position suggests that the 1:2 cocrystal is formed 998



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the measurement of 14N NQR frequencies after 6 months and obtained the same values as in the first measurement. The 14N NQR data show that only the polymorphic phase II has been obtained in our experiments. TMP−Oxalic Acid (1:1). In the cocrystal TMP−OA (1:1), we observed at T = 220 K two sets of 14N NQR frequencies: (4160 kHz, 3030 kHz, 1130 kHz) and (2965 kHz, 2358 kHz, 607 kHz). The first set corresponds to the non-hydrogenbonded nitrogen position in the TMP ring, whereas the second set corresponds to the hydrogen-bonded nitrogen position. The presence of two sets of 14N NQR frequencies shows that one OA molecule interacts with one TMP molecule. The second carboxylic group of the OA molecule may interact with the carboxylic group of a second OA molecule or an intramolecular O−H···O hydrogen bond is formed. TMP−Malonic Acid, TMP−Fumaric Acid, and TMP− Citric Acid. We prepared the cocrystals from the 1:1 methanol solutions. 14N NQR shows at T = 295 K in each of the cocrystals a single nitrogen position with the 14N NQR frequencies equal to (3450 kHz, 2647 kHz, 803 kHz) in TMP− MA, (3473 kHz, 2665 kHz, 808 kHz) in TMP−FA, and (3440 kHz, 2620 kHz, 820 kHz) in TMP−CA. There are two possible explanations of a single nitrogen position: either the 1:2 cocrystals are formed, or each of these di- or tricarboxylic acids interacts with two TMP molecules. In addition, the two nitrogen positions in a TMP molecule are equivalent. To check which of the two possibilities is correct, we prepared the 1:1 molar solutions of the cocrystal formers in methanol and completely removed the solvent. We decided to measure the 14 N NQR spectra in the obtained powder. If the 1:1 cocrystals are indeed formed, we expect to obtain the same 14N NQR frequencies as above. If the 1:2 cocrystals are formed, we expect to obtain a mixture of TMP crystals (50% TMP molecules) and TMP−acid (1:2) cocrystals (50% TMP molecules). In the latter case, we expect to observe in addition to the above 14N NQR frequencies also the 14N NQR frequencies from TMP. The low-frequency part of the 1H−14N NQDR spectrum in the system TMP−fumaric acid is presented in Figure 4. The

hydrogen bond of the second carboxyl group is more favorable than its intramolecular hydrogen bond.

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DISCUSSION The 14N NQR frequencies, quadrupole coupling constant, and asymmetry parameter η in TMP and its cocrystals are presented in Table 1. The lowest 14N quadrupole coupling constant at the hydrogen-bonded nitrogen position (3.55 MHz) is observed in the cocrystal TMP−OA (1:1) formed by the strongest carboxylic acid used. This value is for about 1 MHz lower than in TMP, but it is still relatively high, so the proton transfer O− H···N → O−···H−N+ does not occur in the above systems. It has been shown that in pyridine,26 pyrimidine,16 and pyridazine27 the 14N quadrupole coupling constant reduces to about 1 MHz on protonation. When the nitrogen atom is not hydrogen-bonded, the 14N quadrupole coupling constant is in these systems between 4.6 and 5.1 MHz. Proton transfer is observed below the middle of this region at e2qQ/h < 3 MHz. We assume that the same is true for TMP, so the 14N qudrupole coupling constant well above 3 MHz means that the proton remains at the hydrogen bond donor. The situation is different than in the case of AMP, where we observe proton transfer when strong carboxylic acids are used.16 The reason for different behavior may be in the different pKa values of protonated heterocyclic compounds. For protonated 2-amino4,6-dimethylpyrimidine, the pKa value is equal to 4.85,28 whereas for protonated TMP it is equal to 2.8.29 The data given in Table 1 also suggest that a decrease of the quadrupole coupling constant at the hydrogen-bonded nitrogen position produces an increase of the quadrupole coupling constant at the non-hydrogen-bonded nitrogen position. A correlation between the 14N quadrupole coupling constant in the Lewis base and pKa of the carboxylic acid is shown in Figure 5 for TMP and AMP. The following pKa vales are used: AcA (4.76), Ba (4.20), AnA (3.8630), 4HBA (4.54), 5CSA (2.64), CA (3.14), FA (3.03), MA (2.83), and OA (1.25). For AnA, there are different pKa values published. Here we use the microconstant k22 = 3.86, published in ref 30, which is associated with the dissociation of carboxyl group. It is evident that the quadrupole coupling constant decreases upon decreasing pKa and that hydrogen bonding with the same carboxylic acid produces in TMP a weaker influence on the nitrogen electron orbitals than in AMP. In substituted and hydrogen-bonded pyrimidine, we analyzed the 14N quadrupole coupling tensor in terms of the population of the π-electron orbital and deformation of the lone pair electron orbital.16 We found the two effects are nearly independent. Various ring substituents change mainly the population of the π-electron orbital, whereas hydrogen bonding produces mainly a deformation of the lone pair orbital. A similar analysis can be done also for substituted and hydrogenbonded pyrazine. Unfortunately, there are less experimental NQR data available and the quadrupole coupling tensor of pyrazine has to our knowledge not yet been determined in the gas phase. As the reference, we therefore take the quadrupole coupling tensor determined in solid pyrazine by NQR,31 where the 14N quadrupole coupling constant e2qQ/h and the asymmetry parameter η are equal to 4858 kHz and 0.536, respectively, so the principal values of the quadrupole coupling tensor are equal to qZZ = −4858 kHz, qYY = 3731 kHz, and qXX = 1127 kHz. The sign of qZZ and the orientation of principal axes X, Y, and Z in the molecular frame have been

Figure 4. Low-frequency part of the 1H−14N NQDR spectrum of the sample obtained after the solvent (methanol) is completely removed from the 1:1 molar solution of TMP and fumaric acid. No dip is observed at ν0(TMP) = 1030 kHz.

spectrum is obtained by the technique using multiple frequency sweeps. A dip is clearly observed at νH = ν0(TMP−FA) = 808 kHz. No dip is observed at νH = ν0(TMP) = 1030 kHz, so no TMP crystals are present in the sample. The experiment proves that the 1:1 cocrystals are formed and a fumaric acid molecule bonds to two TMP molecules. In the same way, we confirmed that also in the systems TMP−MA and TMP−CA the 1:1 cocrystals are formed. The present experimental results also show that in the cocrystal TMP−MA (1:1) the intermolecular 999



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Table 1. 14N NQR Frequencies, Quadrupole Coupling Constant e2qQ/h, and Asymmetry Parameter η in TMP and Cocrystals TMP−Acetic Acid (1:2), TMP−Benzoic Acid (1:1), TMP−5-Chlorosalycilic Acid (1:1), TMP−Anthranilic Acid (1:1), TMP−4Hydroxybenzoic Acid (1:2), TMP−Oxalic Acid (1:1), TMP−Malonic Acid (1:1), TMP−Fumaric Acid (1:1), and TMP−Citric Acid (1:1) T (K)

nitrogen position

ν+ (kHz)

ν− (kHz)

ν0 (kHz)

e2qQ/h (kHz)

η

TMP TMP−AcA (1:2) TMP−BA (1:1)

295 178 210

TMP−5CSA (1:1)

170

N N···H N N···H N N···H N N···H NH2 N···H N N···H N···H N···H N···H

3975 3703 4025 3495 4117 3335 3894 3384 2982 3426 4160 2965 3450 3473 3440

2945 2791 2984 2670 3010 2558 2897 2623 2312 2627 3030 2358 2647 2665 2620

1030 912 1041 825 1107 777 997 761 670 799 1130 607 803 808 820

4613 4329 4673 4110 4751 3929 4527 4006 3529 4035 4793 3549 4065 4092 4040

0.447 0.421 0.446 0.401 0.466 0.396 0.440 0.380 0.380 0.396 0.471 0.342 0.395 0.395 0.406

substance

TMP−AnA (1:1)

180

TMP−4HBA (1:2) TMP−OA (1:1)

295 220

TMP−MA (1:1) TMP−FA (1:1) TMP−CA (1:1)

295 295 295

tensor for the presently studied substances and TMP− chloranilic acid (1:1)13 presented in Table 2. Table 2. Principal Values of the 14N Quadrupole Coupling Tensor qZZ, qYY, and qXX and the Parameters xLP and xπ Describing the Deformation of the Lone Pair Orbital and Change of Population of the π-Electron Orbital in TMP and Its Cocrystals Figure 5. Correlation between the 14N quadrupole coupling constant and the pKa of carboxylic acid forming an O−H···N hydrogen bond in TMP (open squares) and 2-amino-4,6-dimethylpyrimidine (full squares) cocrystals.

substance TMP TMP−AcA (1:2) TMP−BA (1:1)

experimentally determined in closely related pyridine and pyrimidine, where qZZ is negative, so we assume that it is negative also in pyrazine. The principal axis Z points along the bisector of the C−N−C angle, i.e., in the direction of the lone pair orbital, whereas the principal axis Y points perpendicular to the ring. The quadrupole coupling tensor q in substituted and hydrogen-bonded pyrazine can be in the principal axis frame X, Y, and Z of pyrazine expressed as ⎛1.127 0 ⎜ q = ⎜0 3.731 ⎜ ⎝0 0 ⎛−0.5 0 ⎜ + xπ ⎜ 0 1 ⎜ ⎝0 0

TMP−5CSA (1:1) TMP−AnA (1:1) TMP−4HBA (1:2) TMP−OA (1:1)

⎞ ⎛−0.5 0 0 0⎞ ⎟ ⎟ ⎜ 0 −0.5 0 ⎟ ⎟⎟ MHz + x LP⎜⎜ 0 ⎟ ⎝0 −4.858 ⎠ 0 1⎠ 0 ⎞ ⎟ 0 ⎟ ⎟ −0.5⎠ (2)

TMP−MA (1:1) TMP−FA (1:1) TMP−CA (1:1) TMP−H2ca (1:1)13

nitrogen position

qZZ (kHz)

qYY (kHz)

qXX (kHz)

xLP (kHz)

xπ (kHz)

N N···H

−4672 −4329

3387 3076

1285 1253

18 268

−334 −520

N N···H N

−4669 −4123 −4751

3370 2896 3482

1299 1227 1269

11 423 −24

−335 −623 −260

N···H N

−3929 −4470

2742 3209

1187 1261

579 169

−699 −437

N···H N···H

−3980 −4037

2764 2834

1216 1203

525 496

−703 −648

N N···H N···H N···H N···H N···H

−4793 −3549 −4065 −4092 −4040 −4190

3526 2382 2835 2854 2840 2960

1267 1167 1230 1238 1200 1230

−51 845 459 436 496 376

−229 −925 −665 −658 −642 −582

In TMP, the deformation of the lone pair orbital is negligible with respect to pyrazine, whereas the population of the πelectron orbital is slightly higher (xπ ≈ −0.3 MHz). A larger population of the π-electron orbital producesdue to the negative electric charge of electrona larger negative value of xπ. The substitution of four hydrogen atoms by four methyl groups is most probably the reason for this difference. At the non-hydrogen-bonded nitrogen positions in cocrystals, the parameter xLP is very small, so the lone pair orbital stays nearly untouched. At the hydrogen-bonded nitrogen position, xLP increases. The maximum value is observed in TMP−OA (1:1)

Here the parameter xLP describes the deformation of the lone pair orbital and the parameter xπ is proportional to the change of population of the π-electron orbital with respect to pyrazine. A quantitative relation between xπ and the change of the population of the π-electron orbital can be calculated either by assuming that an electron in the π-orbital produces an axially symmetric contribution to the quadrupole coupling tensor with the magnitude −9 MHz or, more precisely, by using the quantum chemical calculations. The parameters xLP and xπ are together with the principal values of the quadrupole coupling 1000



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This relation is useful in search of possible combinations of 14N NQR frequencies in the case when the complete NQR spectra are not known.

where it is equal to 845 kHz. This value is significantly lower than in cocrystal AMP−OA where it is with respect to solid AMP larger for 2030 kHz.16 It can also be seen from Table 2 that the parameters xLP and xπ are not independent. Figure 6 presents the correlation between xπ and xLP for TMP and its cocrystals.

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CONCLUSIONS The cocrystals of TMP and a series of carboxylic acids have been prepared, and the complete 14N NQR spectra have been measured. The NQR spectroscopy has been used to check whether the cocrystals are indeed formed and to distinguish between 1:1 ad 1:2 cocrystals. NQR proved that the 1:1 cocrystals form in systems TMP−benzoic acid, TMP− anthranilic acid, and TMP −5-chlorobenzoic acid. In systems TMP−acetic acid and TMP−4-hydroxybenzoic acid, we obtained 1:2 cocrystals. In the latter case, we observed no polymorphic phases. In both systems, the two nitrogen positions in a TMP molecule are equivalent. In the cases of di- or tricarboxylic acids, we obtained the 1:1 cocrystals. In the system TMP−oxalic acid, the acid molecule binds to a single TMP molecule. In the systems TMP−malonic acid, TMP− fumaric acid, and TMP−citric acid, an acid molecule binds to two TMP molecules and the two O−H···N hydrogen bonds formed by a TMP molecule are equivalent. The lowest 14N quadrupole coupling constant observed in the present systems is about 3.5 MHz, which shows that the proton transfer from the carboxylic acid to the TMP molecule does not occur. This is different than in the case of AMP where we observed proton transfer when interacting with oxalic acid, malonic acid, and 5-chlorosalicylic acid. A correlation of the 14N quadrupole coupling constant and the pKa value of the carboxylic acid has been observed. The quadrupole coupling tensor in TMP cocrystals has been analyzed in terms of the deformation of the electron lone pair orbital and population of the π-electron orbital. The results are compared to the results obtained in the case of the cocrystals of AMP. In the case of TMP, hydrogen bonding with a given carboxylic acid produces a significantly lower deformation of the lone pair orbital than in the case of AMP. The change of the population of the π-electron orbital and the deformation of the lone pair electron orbital are correlated in hydrogen-bonded TMP and uncorrelated in hydrogen-bonded AMP. The principal values of the quadrupole coupling tensor in hydrogen-bonded TMP are correlated. The correlation relations are not very much different from the similar correlation relations observed in hydrogen-bonded pyridine.

Figure 6. Correlation between the population of the π-electron orbital (xπ) and the deformation of the lone pair electron orbital (xLP) in TMP and its cocrystals.

A nearly linear correlation between the two parameters is observed which can be expressed as xπ = −0.29 MHz − 0.75x LP (3) From the point of view of NQR, it is also interesting to see whether the principal values of the 14N quadrupole coupling tensor in TMP and its cocrystals correlate. This may be useful in search of the 14N NQR frequencies and in assigning the NQR lines to various nitrogen positions in the case of a complex 14N NQR spectrum. The correlation of qXX and qYY versus qZZ for TMP and its cocrystals is presented in Figure 7.

Figure 7. Correlation of qXX and qYY vs qZZ in TMP and its cocrystals.

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A nearly linear correlation of the principal axes of the quadrupole coupling tensor is observed, which can be expressed as

The authors declare no competing financial interest.

qYY = −0.99 MHz − 0.94qZZ qXX = 0.99 MHz − 0.06qZZ

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REFERENCES

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The coefficients in these expressions are close to the coefficients obtained in the case of hydrogen-bonded pyridine,26 where the correlation expressions well describe the behavior of the principal values of the quadrupole coupling tensor in the whole range between pyridine molecule in the gas phase through the range of hydrogen-bonded pyridine to the pyridinium ion. From the correlation expressions for the principal values of the quadrupole coupling tensor, it is possible to calculate the correlation expressions for the 14N NQR frequencies ν+ and ν− in hydrogen-bonded TMP. The result is ν− = 0.765 MHz + 0.546ν+

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Notes

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Article

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Nuclear Quadrupole Resonance Investigation of Hydrogen Bonding in

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