Influence of the Local Chemical Environment in the Formation of

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Influence of Local Chemical Environment in Formation of Multicomponent Crystals of L-Tryptophan with N-Heterocyclic Carboxylic Acids: Unusual Formation of Double Zwitterions Babulal Das, and Hemant Kumar Srivastava Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 31 May 2017 Downloaded from http://pubs.acs.org on June 1, 2017

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Crystal Growth & Design

Influence of Local Chemical Environment in Formation of Multicomponent Crystals of LTryptophan with N-Heterocyclic Carboxylic Acids: Unusual Formation of Double Zwitterions Babulal Das*, Hemant Kumar Srivastava* Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India, Email: [email protected], [email protected] Tel: +913612582337; +913612582302; Fax: +913612582349. Abstract: Formation of multicomponent crystals (MCCs) of L-tryptophan (TRP) with Nheterocyclic carboxylic acids such as 2-picolinic acid (PA) and its 3- or 4- substituent isomers (nicotinic acid or isonicotinic acid), pyrazinecarboxylic acid (PZCA), 2,3-pyrazinedicarboxylic acid (2,3-PZDCA), 2-quinaldic acid (QA) and its 3-subsituent isomer (3-QA) is investigated in this manuscript. The investigation results in four multicomponent solid forms of the amino acid with coformers where the electron withdrawing functional group (-COOH) were present in ortho- substituent to N-heterocyclic rings. The isomers of PA or QA having –COOH at meta- or paraposition failed to produce new phases. These solid phases were identified by PXRD results and the MCCs derived from 2-picolinic acid (1) and 2,3-pyrazinedicarboxylic acids (3) were further characterized with single crystal X-ray diffraction. The crystal structure of TRP-PA (1) reveal a rare form of co-crystal where both the amino acid and the picolinic acid are in zwitterionic form. Further, in our surprise, the amino acid appears to undergo change in absolute configuration during co-crystallization. Crystal TRP-2,3-PZDCA (3) is observed as salt where the amino acid exists in cationic form and the carboxylic acid exists in anionic form. It is observed that the complementary H-bonding between the py-N/ortho- -COOH of the coformers with the α-NH3+/α-COO- group of L-tryptophan primarily drive the co-crystallization process. DFT calculations support the experimental observations as lower total energy and higher interaction energy values are obtained for the successfully synthesized MCCs. The solid state fluorescence of TRP (known as intrinsic fluorescence probe) shows that 2,3-PZDCA is an effective quencher. Keywords: Multicomponent crystals, L-tryptophan, N-heterocyclic carboxylic acids, Chemical environment, Double zwitterions, Absolute configuration, Interaction energy, fluorescence quenching, DFT calculations.

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Introduction Understanding of chemical and crystallographic environment of the components is the fundamental criteria to design and creation of novel crystalline materials. The concept of supramolecular synthon, the effect of functional groups (electron withdrawing or donating) and the difference in pKa values of the individual components are the key factors that influence the creation of such materials.1-7 Hammett substituent constants (σ) are often used to quantify electron withdrawing and donating capability of functional groups to correlate the co-crystal formation.8 The inductive effect controls the outcome of co-crystallization process.9 Further, the influence of local chemical environment such as position isomerism also allow complementary recognition between two different molecules.10 This study also presents the role of functional groups in tuning the physicochemical properties of the adducts formed during the complexation process. However, the design of such materials with desired properties is still a challenge. The molecular shapes, competition of intermolecular interactions among different functional groups, steric hindrance and solvent effects make the situation often more complicated. This has encouraged chemists to explore various factors associated with different chemical and crystallographic environment controlling the formation of multicomponent crystals (MCCs).11 A better understanding on experimental and computational investigations will contribute further to the creation of such novel functional materials. In the present study, we investigated the MCCs of L-tryptophan (TRP) with some Nheterocyclic carboxylic acids influenced by local chemical environment of the coformers. The attempted co-crystallization was successful with those coformers where the electron withdrawing functional group (-COOH) was present in ortho- substituent to pyridine or pyrazine ring such as picolinic acid (PA), 2-pyrazinecarboxylic acid (PZCA), 2,3-pyrazinedicarboxylic acid (2,3PZDCA) and 2-quinaldic acid (QA) by both solution and solid state routes (Fig. 1). The amino acid failed to produce new phases with nicotinic acid and isonicotinic acid (isomers of PA) or 3quinolinecarboxylic acid (isomer of QA), where the carboxyl group is located in meta- or paraposition under identical conditions. L-tryptophan, an essential α-amino acid, contains α-NH2, αCOOH and a side chain indole ring. TRP, used as a supplement to treat insomnia and depression, acts as a biochemical precursor for serotonin, melatonin and niacin.12-13 It is a reliable fluorescence probe for determination of protein structure and dynamics including the


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conformation changes and ligand binding.14-17 On the other hand, the coformers PA and QA are biologically associated with TRP. PA, an endogenous metabolite of TRP, known to possess a wide range of neuroprotective, immunological, and anti-proliferative affects within the body. QA, found in human urine, is a product of TRP catabolism via kynurenic acid.18-19 The amino acid can be used to aggregate with various coformers because of amphiphilic nature, hydrogen bonding capability, face-to-face π–π stacking and other interactions e.g. NH···π, CH···π etc. However, despite the possibilities of all these interactions, surpamolecular host-guest complexes of tryptophan are limited. A recent study reported that there are twelve structures with zwitterionic tryptophan; nine of them of TRP, one of D-tryptophan with naproxen and the remaining two are of pure DL-tryptophan.20-32 Additionally, the number of structures with cationic TRP are also limited.33-37 The indole ring of TRP is usually difficult to ionize and only strong acids or bases can protonate or deprotonate the ring. Thus, the reactivity of the amino acid is mainly dependent on -COOH and -NH2 group. TRP exists in zwitterionic form under most biological conditions and thus a less number of multicomponent structures were found. This expresses that selection of coformers to stabilize the amino acid is crucial and quantitative understandings at the molecular level interactions deserve special attention. With this background, the current work explores the influence of local chemical and crystallographic environment in the formation of these multicomponent solids in order to examine the structural and conformational changes and the variation in fluorescence behavior of the amino acid in the solid state. DFT calculations were performed on MCCs and hypothetical structures to rationalize the experimental findings.



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Figure 1. Structural formulas of (a) L-tryptophan (TRP), (b) 2-picolinic acid (PA), (c) 2pyrazinecarboxylic acid (PZCA), (d) 2,3-pyrazinedicarboxylic acid (2,3-PZDCA), and (e) 2quinaldic acid (QA).

Experimental Materials: L-tryptophan (98%), 2-picolinic acid (pyridine 2-carboxylic acid) (99%), nicotinic acid (pyridine 3-carboxylic acid) (98%), isonicotinic acid (pyridine 4-carboxylic acid) (99%), pyrazinecarboxylic acid (99%), 2,3- pyrazinedicarboxylic acid (97%), quinaldic acid (quinoline 2-carboxylic acid) (98%), quinoline 3-carboxylic acid (98%) were purchased from SigmaAldrich Co., which were of the best available purity and were used without further purification. Ethanol (Bengal chemicals) and Milli Q water from Merck Millipore was used in all experiments. Preparation of L-tryptophan MCCs Solid state grinding as well as conventional solvent evaporation methods in polar solvents such as MeOH, EtOH and H2O were used for screening the solid phases. TRP and PA were ground together in 1:1 molar ratio with a few drops of water in a mortar. Despite of the bulk solids of each coformers being white in color, the resulted ground mixture appeared as yellow in color. This preliminary observation led to the formation of new phase and then tried to crystallize it by dissolving in various solvents such as methanol, ethanol, DMF and DMSO in pure form and in 1:1 ratio with water. Greenish yellow needle-like crystals were harvested after 4-5 days. Similar experiments attempted with other two isomers of PA such as nicotinic acid and isonicolinic acid failed to produce new phases which is confirmed PXRD results. Liquid assisted grinding of TRP with PZCA and 2,3-PZDCA independently in equimolar ratio resulted in violet colored damp mass. The mass is found soluble in EtOH/H2O mixture. Yellow block-shaped crystals were harvested from TRP-2,3-PZDCA solution after a week. No single crystal could be grown from TRP-PZCA, but formations of new solid phases were confirmed by powder diffraction patterns. Grinding of QA and TRP in equimolar ratio for two minutes with the addition of 10 µL of MeOH was sufficient to note appearance in solid phase. This TRP-QA solid phase exhibit a different powder XRD pattern from initial pure components, but single crystal couldn’t be grown in our numerous crystallization attempts.


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Figure 2. Optical micrograph of the crystals 1 and 3 The solid mixture derived from quinoline 3-carboxylic acid and the amino acid unable to give new phase under identical conditions. Alternatively, the new solid phases or the MCCs obtained from grinding are consistent with that obtained from solution evaporation method. The crystal morphologies of TRP-PA (1) and TRP-2,3-PZDCA (3) are shown in Fig. 2. Physical measurements FTIR (Fourier transform infrared) spectra were recorded with a Perkin Elmer (Spectrum two) spectrophotometer (4000 - 500 cm-1). Powder X-ray diffraction (PXRD) data were recorded using a Bruker D2 Phaser diffractometer with Cu Kα (1.542 Å) radiations with the scan range 2θ = 5 to 50º and step size 0.02º. DSC (Differential scanning calorimetry) analyses were performed on a TA Instruments Q20 differential scanning calorimeter under nitrogen environment at a heating rate of 5 ºC / minute over a temperature of 30 to 400 ºC. Solid state UV-visible transmission

spectra

were

recorded

using

PerkinElmer

Lambda-750

UV-VIS-NIR

spectrophotometer. Crystal morphology were taken with an optical microscope (BX-51, Olympus, Japan) equipped with CCD camera (XC10). Horiba Fluoromax-4 spectrometer designed with solid sample holder at an angle of 60o is used to measure the fluorescence of the finely powdered samples in the solid state. Single crystal X-ray diffraction Single crystal data of MCCs 1 and 3 were collected on Oxford SuperNova microfocus based single crystal difractometer at 293.0 K where the data refinement and cell reductions were carried out by CrysAlisPro software. Structures were solved by direct methods and were refined by full-matrix least-squares on F2 using SHELXL2014 software. All the non-H atoms were refined in the anisotropic approximation against F2 of all reflections. The H-atoms attached to N and O atoms in these crystals were located in the difference Fourier synthesis maps, and refined



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with isotropic displacement coefficients. Absorption was found negligible in each crystal. Crystal data and details of the final refinement parameters are summarized below. Crystal data for 1: C17H21N3O6, M = 363.37 gmol-1, Orthorhombic, space group P212121, a = 7.2828(13) Å, b = 8.8085(10) Å, c = 26.696(4) Å, V = 1712.6(4) Å3, Z = 4, F000 = 768, µ = 0.108 mm-1, T = 296 K, 4402 reflections collected, 2844 unique reflections (Rint = 0.0439), 1676 observed reflections [I > 2σ(I)], R1(obs) = 0.0690, wR1(obs) = 0.1220, R2(all) = 0.1280, wR2(all) = 0.1629, 256 parameters refined, Final GOF= 0.949, CCDC 1537895. Crystal data for 3: C17H20N4O8, M = 408.37 gmol-1, Monoclinic, space group P21, a = 6.9474(4) Å, b = 17.6071(10) Å, c = 8.0249(4) Å, β = 104.931(6)o, V = 948.49(10) Å3, Z = 2, Dc = 1.430 gcm-3, µ = 0.115 mm-1, T = 296(2) K, 3370 reflections collected, 2209 unique reflections (Rint = 0.0237), 1849 observed reflections [I > 2σ(I)], R1(obs) = 0.0435, wR1(obs) = 0.0927, R2(all) = 0.0546, wR2(all) = 0.1033, 299 parameters refined, Final GOF = 1.066, CCDC 1537896. Computational Methodology: Geometries of all the considered structures have been fully optimized in gas phase and in solution phase at B3LYP/6-31G(d) level of theory using the Gaussian-09 program package.38 The Polarizable Continuum Model (PCM) using the integral equation formalism variant (IEF-PCM) is applied for performing all the calculations in solution (water medium, dielectric constant ∈ = 80.1) phase.39-40 Frequency calculations at the same level of theory characterize the obtained stationary points as minima on the potential energy surface.

Results and Discussion Identification of MCCs Solid state grinding of the amino acid with different coformers results in changes in color of ground mixture. The changes in color may indicate appearance of new materials having a different phase when compared to that of starting materials (detailed in the experimental section). These ground powders were then analyzed by powder X-ray diffraction and the thermal behaviour was accessed by DSC. The X-ray diffraction of solid powders of TRP-PA (1) and TRP-2,3-PZDCA (3) (obtained from independent reactions) reflected distinct powder pattern with the formation of new peaks from those of their parent compounds. The diffraction patterns of these solid phases (Fig. S1) are in good agreement with those simulated from the single-


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crystal structures (structural analysis discussed later). This also indicated the bulk purity of the new solid phases. The DSC thermogram displayed sharp melting endotherms for 1 and 3, indicating highly crystalline materials (Fig. 3). The MCC 1 showed three prominent exothermic peaks. The peak at 94.5 ºC attributes to dehydration, a sharp peak at 247 ºC corresponds to its melting followed by a broad peak due to thermal decomposition. The crystal 3 exhibits similar exothermic peaks with melting temperatures at 101 ºC and 208 ºC respectively. The PXRD data for the TRP-PZCA (2) and TRP-QA (4) presented in Fig. 4, showed poor crystallinity resulting in broader peaks bearing new reflections when compared to their pure forms and thus indicating formation of new phase. The hypothesis of the formation of new phase as derived from PXRD data was further supported by the appearance of single melting point in DSC (Fig. S2). Single crystal of these two new identified solid forms could not be grown even after attempting with different combinations, solvents and crystallization technique. The PXRD patterns of TRP-NA, TRP-INA (isomers of PA) or TRP-3QA (isomer of QA) combinations obtained via solution evaporation showed no distinct or new peaks as compared to their parent counterparts, suggesting them to be physical mixture only (Fig. S3). Similarly, the PXRD of the solventassisted grinding mixture also resulted in similar results. The investigated compositions, cocrystallization experiments, nature of powder materials or crystals and the techniques used to characterize them are summarized in table 1.

Figure 3. DSC heating curves for TRP-PA (1) and TRP-2,3-PZDCA (3) (heating rate 5 ºC/min)



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Figure 4. PXRD patterns of MCCs TRP-PZCA (2) and TRP-QA (4) along with the amino acid and acidic coformers. Table 1. Summary of investigated compositions, co-crystallization experiments, nature of powder materials and characterization techniques investigated

co-crystallization

color and morphology

forms a

characterization

compositions

experiments

of materials / crystals

MCC?

techniques

Greenish yellow powder / needle type crystals White powder White powder

yes

FTIR, DSC, PXRD, SXRD

no no

DSC, PXRD DSC, PXRD

Violet sticky solids

yes

TRP-3-QA

White powder

no

FTIR, DSC, PXRD DSC, PXRD

TRP-PZCA

Violet solids

yes

FTIR, DSC, PXRD

TRP-2,3-PZDCA

Greenish yellow solids / block shaped crystals

yes

FTIR, DSC, PXRD, SXRD

TRP-PA

TRP-NA TRP-INA TRP-QA

Neat and liquid assisted grinding / solvent evaporation method

Structural discussion of TRP-PA (1) The structural analysis was performed on a needle-like (edge 18.0 kJ mol-1 more stable than the hypothetical TRP-NA or TRP-INA structures. Similarly, >28.0 kJ mol-1 higher energy of TRP-3-QA system compared to TRP-QA shows that a MCC is not favorable between TRP and 3-QA. We computed the interaction energy (IE) values between the crystal partners by using the supramolecular approach as described in the footnote of Table 3.75-76 The IE values for the successfully synthesized MCCs vary from ~ 77.8 to ~ 90.0 kJ mol-1, whereas the coformers that failed to produce co-crystals showed much lower IE values (~ 36.0 kJ mol-1). These calculations indicate that the preference for co-crystallization is highest for N-heterocyclic coformers with -COOH at ortho- position which is capable of complementary hydrogen bonding to the amino acid molecule. The


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coformers having -COOH at meta- or paraposition appears to form isolated hydrogen bonding patterns resulting in a lesser IE value, which may not be adequate for complexation.77-79

Table 3: Stability in terms of energy difference and interaction energy of the crystal systems Crystal system TRP-PA TRP-NA TRP-INA

Stability (kJ/mol) Solvent Gas 0.0 0.0 +17.99 +21.34 +23.01 +30.54

IE (kJ/mol) Solvent 81.17 35.98 35.15

TRP-QA TRP-3-QA

0.0 +29.29

0.0 +28.03

82.84 35.98

TRP-PZCA

0.0

0.0

89.96

TRP-2,3-PZDCA

0.0

0.0

77.82

TRP-PA, TRP-QA, TRP-PZCA and TRP-2,3-PZDCA was experimentally observed. TRP-NA, TRP-INA and TRP3-QA are hypothetical structures. Stability is the difference in total energies of experimentally observed and hypothetical structures. IE is calculated using the equation IE = (EAB) – (EA+EB). ‘EAB’ is the total energy of the crystal, ‘EA’ is the total energy of amino acid and ‘EB’ is the total energy of the coformer. ‘Solvent’ indicates that the given values are obtained from calculations in water medium using IEF-PCM theory. ‘Gas’ indicates that the given values are obtained from gas phase calculations. All the calculations were performed at B3LYP/6-31G(d) level of theory. Please see Table S2 for details.

Conclusions The multicomponent crystal structures and solid forms described here combined with our earlier study demonstrate a general behavior of TRP and its co-crystallization with Nheterocyclic carboxylic acids. This study demonstrates that the co-crystallization occurs when the coformers contain a carboxylic functional group specifically at ortho- position irrespective of their pKa value. The complementary H-bonding between -NH3+ and -COO– of the amino acid with pyridine nitrogen and ortho- carboxyl groups of acidic coformer govern the cocrystallization process. The π-stacking interactions and crystal hydrates further influences the stability of these MCCs. The physicochemical properties of these solids appear to be influenced by local chemical and crystal environment of the coformers. The double zwitterionic nature of crystal 1 provides an added level of structural flexibility that may influence the physicochemical properties of the crystal. The combination of dipole–dipole interactions, intramolecular charge transfer, and packing effect may serve as the basis for plausible change in absolute configuration



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of the amino acid. The DFT calculations support the experimental results as total energies and interaction energies are considerably higher for the successfully obtained MCCs. All the crystals represent the TRP fluorescence profile with variation in quenching intensity in the solid state. The π-π stacking arrangement between the amino acid and the coformer is attributed to this quenching, although the quenching of TRP fluorescence by exposure to external quenchers is described with various mechanisms.

Acknowledgements The authors thank Department of Chemistry and Central Instruments Facility of Indian Institute of Technology Guwahati for all the facilities. HKS is thankful to DST-SERB for the financial assistance (Ramanujan Fellowship SB/S2/RJN-004/2015). We thank Dr. C. V. Sastri for valuable suggestions. Supporting Information The CIF files of the two MCCs reported here are deposited to CCDC and have their CCDC Nos. 1537895 and 1537896. Powder XRD patterns of 1 and 3 (simulated and experimental), DSC plots (2 and 4), FTIR spectra of dehydrated forms are available. DFT based energies and optimized coordinates and other details are available.

Corresponding Authors Babulal Das (Email: [email protected] ) and Hemant Kumar Srivastava (Email: [email protected])

Author Contributions The manuscript was written through contributions of both the authors. Both the authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interest.

References


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For Table of Contents Use Only Influence of Local Chemical Environment in Formation of Multicomponent Crystals of LTryptophan with N-Heterocyclic Carboxylic Acids: Unusual formation of Double Zwitterions Babulal Das*, Hemant Kumar Srivastava*

Synopsis: Experimental observations rationalized by DFT calculations showed the formation of multicomponent crystals of L-tryptophan with N-heterocyclic carboxylic acids having carboxylic group at ortho- position, primarily driven by the complementary hydrogen bonding. Unusual formation of double zwitterions, assessment of supramolecular synthons and solid state spectroscopic properties are reported.


Influence of the Local Chemical Environment in the Formation of

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