Imagination Materializes with Serendipity: Third Polymorph of N-Amino 1,8-Naphthalimide

doi:10.21203/rs.3.rs-7535669/v1

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Imagination Materializes with Serendipity: Third Polymorph of N-Amino 1,8-Naphthalimide

https://doi.org/10.21203/rs.3.rs-7535669/v1

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Synthon polymorphs are less encountered in the literature. It is challenging to prepare synthon polymorphs same synthon organized in different manners. We describe here the third polymorph of N-amino 1,8-naphthalimide that has R²₂(10) synthon of symmetry-related molecules assembled as a chain similar to a reported polymorph, which had symmetry-independent molecules; this made the difference in the self-assembled structure of the two polymorphs. The assemblies of three polymorphs of the compound, as well as the DFT-optimized energies of the dimeric assemblies of the two polymorphs, were also determined and compared. The new polymorph was obtained through the decomposition of 1-(2,4-dichlorophenyl)-3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)thiourea (DTU) in dimethylformamide solution that was kept at 80°C. When the solution was cooled, crystals of the concomitant polymorphs of two closely related forms were obtained, providing a new methodology for preparing the polymorph. Besides these, the structure of DTU was analysed to show the prerequisites for the alignments of the stacked naphthalimide rings in the starting compound to easily transform to the alignments of the stacking rings observed in the concomitant polymorphs.

Naphthalimide

Synthon polymorph

Self-assembly

Energy Calculation

Same compound or assembly of a particular composition but with dissimilar solid-state structures are polymorphs [1–4]. They influence the efficacy of drugs [5–9], Color [10–12], and magnetic properties [13–15]. The polymorphs have also established roles in utility-oriented materials such as electronic materials [16], fertilizers [17] etc. Conformation [18–19] as well as packing polymorphs [20–22] are observed in assemblies of a single conformation of a molecule extending to three dimensions. Due to tightly held ions or molecules in a crystal lattice of a crystalline solid, conformers or energetically less preferred geometry gets stabilized. Though the infinite numbers of polymorphs from one system may be imagined but the question remains how many forms can be obtained in reality, or to make a prediction when one of the forms will be formed. Polymorphs with variations of supramolecular synthons termed as synthon polymorph [23–27] are fewer in number also have a significant role in modulating properties [28]. Concomitant polymorphs [29] and disappearing polymorphs [30]. Different methodologies such as solution crystallization [31–32], solvent drop grinding [33], capillary [34], nano-confinement [35], ball-milling [36], etc, are routinely adopted to crystallize a polymorph. As per the literature, polymorph design has many questions to answer, starting from predictive forms and rationale in crystallization [37]. However, there are many processes, such as cross-nucleation of multiple forms [38], thermal transformations [39], and facial growth leading to morphological differences [40], which add complications in understanding polymorphs. Thus, there is a search for newer methodologies to prepare polymorphs. For example, two polymorphs of N-amino 1,8-naphthalimide are reported in the literature [41–42]. They are synthon polymorphs, one having hydrogen-bonded dimers, with R¹₂(5), and the other having R²₂(10) types of dimers constituting a chain as illustrated in Figures 1a and 1b. A preliminary look at the second polymorphs shows that there are two sets of symmetry-independent hydrogen-bonded dimers A and B, as marked in Fig. 1b at alternate places of a chain-like structure. So, there is a possibility of another polymorph that would have the chain with all symmetry-related molecules. Serendipitously, we obtained the new polymorph of N-amino 1,8-naphthalimide from the decomposition of 1-(2,4-dichlorophenyl)-3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)thiourea in dimethyl formamide solution, in a consistently reproducible manner. We report the characteristics of the new polymorph of the N-amino-1,8-naphthalimide by bringing out the distinguishable features from the other two forms.

General:

The hot-stage microscopic studies were carried out on a polarizing optical microscope (Nikon Eclipse LV100POL) equipped with a programmable hot stage (Mettler Toledo FP90). For this purpose, a clean glass slide with a coverslip to place the sample in between to record the polarizing optical microscopic images (heating rate = 10°C/min). Thermogravimetric analysis was done on a PerkinElmer thermogravimetric analyzer TGA 4000 (heating rate = 10°C/min). The differential scanning calorimetry was performed on Mettler Toledo DSC1 equipment, and measurements were carried out under a nitrogen atmosphere. The transition temperatures obtained from calorimetric measurements of the first heating and cooling cycles, conducted at a rate of 10°C/min. Infrared spectra of the solid samples were obtained with a PerkinElmer Spectrum FT-IR spectrophotometer (USA) by using the ATR method. Powder X-ray diffraction patterns were recorded using a Bruker powder X-ray diffractometer D2-phaser. DFT calculations were performed by Gaussian 09 software, and calculations were performed at the B3LYP level and using the 631-G++(d,p) basis set.

Synthesis

The compound 1-(2,4-dichlorophenyl)-3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)thiourea (DTU) was prepared by following the literature procedure [43]. It was prepared by reacting a 2,4-dichlorophenyl isothiocyanate (202.4 mg, 1 mmol) and N-amino-1,8-naphthalimide (212 mg, 1 mmol) in DMF (15 mL). After stirring the reaction mixture for 8 hs, the solution was kept for crystallization by slow evaporation in an undisturbed condition. After 3–4 days, the crystals of DTU were formed and were collected by decantation of the supernatant layer. Approximately 20% of pure crystals were obtained. The compound was characterized by recording NMR, IR mass, and finally determined by single crystal structure. Yield % 84. ¹HNMR (600 MHz, CDCl₃, ppm): 8.63–8.8.62 (d, J = 6Hz, 2H), 8.24–8.22 (d, J = 8Hz, 2H), 7.78–7.76 (J = 8 Hz, t, 2H), 5.54 (s, 2H).

Formation of concomitant polymorphs:

DTU (0.4 g, mmol) was dissolved in DMF (15 mL, ≤ 0.10% water), the solution was placed in an oil bath maintained at 80°C by using a variac for 2 hs, and then the hot solution was allowed to cool to reach room temperature in undisturbed conditions and left for crystallisation. After 30 minutes, the crystals of Polymorph-3 along with Polymorph-2 were crystallised out. Yield: 84%. ¹HNMR (600 MHz, CDCl₃, ppm): 8.63–8.8.62 (d, J = 6 Hz, 2H), 8.24–8.22 (d, J = 8Hz, 2H), 7.78–7.76 (t, J = 8Hz, 2H), 5.54 (s, 2H). IR (neat, cm^− 1) 3309 (w), 3232 (w), 1696 (s), 1638 (s), 1614 (s), 1581(s), 1549 (s), 1512 (m), 1412 (s), 1380 (s), 1360 (m), 1234 (s), 1174 (s), 1147(m), 1096 (m), 1067 (m), 1025(w), 981(m), 898 (m), 882 (s), 841(s), 768 (s), 727(s), 693 (w), 636 (w), 538 (s), 404 (s).

Structure determination

Single-crystal X-ray diffraction data of the DTU and Polymorph-3 were collected at 296 K by using Mo Kα radiation (λ = 0.71073 Å) on a Bruker Nonius SMART APEX CCD diffractometer equipped with a graphite monochromator and an Apex CCD camera. Data reductions and cell refinements were performed using SAINT and XPREP software. Structures were solved by direct methods and were refined by full-matrix least-squares on F² using SHELXL-2014 software. All non-hydrogen atoms were refined in an anisotropic approximation against F² of all reflections. Hydrogen atoms were placed at their geometric positions by riding and refined in the isotropic approximation. The crystal data and refinement parameters are listed in Table 1S.

Hirshfeld surface analysis

Hirshfeld surfaces of all the polymorphs were calculated using CrystalExplorer version 17.5. The Finger-print plots were generated by setting parameters as 𝑑_norm = (𝑑_i−𝑟_i^vdW)/𝑟_i^vdW+(𝑑_e−𝑟_e^vdW)/𝑟_e^vdW where d_e and d_i are the distances from the Hirshfeld surface to the nearest atoms outside and inside the surface. Both d_e and d_i are normalized by the van der Waals radius of the atoms involved. r_i^vdW and r_e^vdW are the van der Waals radii of the atoms. When the d_norm value is negative (demarcated by a red spot), then the intermolecular contacts between atoms are shorter than the sum of their van der Waals radii.

Structural comparisons among the polymorphs:

The crystals of the concomitant polymorphs of N-amino-1,8-naphthalimide were obtained serendipitously from the composition of thiourea derivative 1-(2,4-dichlorophenyl)-3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)thiourea (DTU) at 80°C as illustrated in Scheme 1. The

powder pattern of the bulk crystals of the has all the principal peaks matching the theoretically generated pattern from the crystallographic information files of the two polymorphs as given in Fig. 5S. Our attempt to get only one form from the mixture was not successful. The crystals of the Polymorph-3 were picked up randomly and manually for structure determination, the crystals belonged to the orthorhombic Pna2₁ space group. The unit cell volumes of the three polymorphs of the N-amino 1,8-naphthalimide were similar. The unit cell parameters and crystal densities of are compared in Table 1. It may be mentioned that one of the reported polymorphs of N-amino-1,8-naphthalimide, designated here as Polymorph-2, had symmetry-independent molecules within the unit cell. In contrast, the other reported one, designated as Plymorph-1, had all symmetry-related molecules in the unit cell. The third form also contains all symmetry-equivalent molecules in the unit cell. The hydrogen-bonded N-amino-1,8-naphthalimide molecules of this polymorph are arranged as linear chains involving both the NH-NC = O faces of the pairs. The chain has

Table 1
Comparative unit-cell data of the three polymorphs
Polymorph	Polymorph-1	Polymorph-2	Polymorph-3
Space group	Orthorhombic Pna2₁	Triclinic P -1	Orthorhombic Pna2₁
Length of cell axis (Å)	a = 13.296(2), b = 18.408 (4), c = 3.781 (11)	a = 7.307(6), b = 9.364 (7), c = 14.655 (10)	a = 7.204(18), b = 16.373 (4), c = 7.996 (19)
Angles (°)	α = β = γ = 90.00	α = 81.676(3), β = 80.506(3), γ = 69.460(3)	α = β = γ = 90.00
Volume (Å³)	925.5 (4)	922.15 (12)	943.1(4)
Density (gcm^− 3)	1.518	1.523	1.495

hydrogen-bonded synthons with R²₂(10) graph-set notation as shown in Fig. 2a. The synthons have N2-H^…O1{d_D…A, 3.0579(8)Å; <DHA, 154°) and N2-H^…O2 {d_D…A, 3.0671(8)Å, <DHA, 159°} hydrogen bonds. The Polymorph-2 and Polymorph-3 have similarity in assembling, as both have chain-like structure; the difference arises from the two alternative pairs of symmetry independent molecules in the Polymorph-2, each associated as pairs with two independent R²₂(10) synthons (Fig. 1b), held to one another with distinguishable hydrogen bond parameters. The naphthalimide rings of independent neighboring chains of the Polymorph-3 are in parallel stacks. Considering the amino-group as the head and the naphthalene ring part as the tail, such stacking dipoles are aligned oppositely, showing a head-to-tail arrangement with a centroid-to-centroid distance of 3.649 Å. This distance is suggestive of weak interactions among the rings [44]. The Polymorph-1 had head-to-head arrangements, and Polymorph-2 had head-to-tail stackings in pairs formed among the neighboring naphthalimide rings. In the literature, there are examples of polymorphs with eclipsing 1,8-naphthalimide rings with dipoles aligned oppositely, as well as one having dipoles of rings oriented in the same direction [45]. On the other hand, different positional isomeric naphthalimide-based compounds having flexible tethers generate large variations in the stacks between the naphthalimide rings [46–47], and many polymorphs of naphthalimide derivatives with different orientations prepared by changing the crystallization process have wide variations in colors [48–49]. In the present example, the conformational adjustment can occur through the rotation of the N-N bond of the N-NH₂ unit, changing the orientations of the hydrogen bond donor N-H bonds. In fact, this was a reason, together with the orientations of the rings in proximity, have caused the distinctions in the scheme of hydrogen bonds in packings of the three polymorphs.

Hirshfeld surfaces, total energies and DFT optimized energies:

The Hirshfeld surface analyses [50] of each polymorph were performed to distinguish the type of contacts in each case. The percentage of different interactions within a distance of 3.8 Å of the surface. The atoms in the vicinity of the surface are shown in Fig. 3. Different

percentages of contacts are listed in the supporting table and the pie-diagrams as for comparison are shown in Fig. 4a-c. They show that major contributions in the polymorphs were from contacts of hydrogen atoms and are comparable. The All_in-O in the three polymorphs was in order 2 > 1 > 3, and the All_in-C was 3 > 1 > 2. The Polymorph-1 and Polymorph-3 had identical nitrogen contacts with atoms inside the surface, whereas they had 0.8% less All_in-N contacts. This was due to differences in the orientation of the molecules of the symmetry-independent molecules within the lattice. Though the Polymorphs-1 and Polymorph-2 had differences in All_in-O and All_in-N, the total weight of these two contacts was higher in Polymorph-1 than the Polymorph-3, showing that the former had more amounts of moderate hydrogen bonds.

The dispersive and repulsive as well as total energies of the polymorphs by using Crystal Explorer with the B3LYP functional at the 6-31G(d,p) level. The respective dispersive energies are Polymorphs-1 to 3 were − 66.0 kJ/mol, -11.0 kJ/mol, and − 70.3 kJ/mol, whereas the respective repulsive energies were 30.8 kJ/mol, 21.2 kJ/mol, and 38.8 kJ/mol. Whereas the respective total energies − 48.7 kJ/mol, -25.6 kJ/mol, and − 51.2 kJ/mol. This showed that the stability of the polymorphs was of the order Polymorph-3 > Polymorph-2 > Polymorph-1.

The energy of each molecule in the conformation as observed in each polymorph was calculated by DFT using the B3LYP functional at the 6–31 + + G(d,p) level. It was found that each conformer has different energies, and the energies of the two symmetry-independent molecules differed by 5.2 kJ/mol from one another, as illustrated in Fig. 5a.. On the other hand electronic energy of the Polymorph 2 > 3 > 1. But the energy difference between the Polymorph-2 and Polymorph-3 was very small. The energy of each polymorph was also optimized in the gas phase by DFT calculation with B3LYP functional at 6–31 + + G(d,p) level. It was found that the optimized energies of Polymorph-1 and Polymorph-3 were the same; hence, the hydrogen-bonded dimers of Polymorphs-2 and Polymorph-3 were independently determined. This has revealed that polymorph-3 is 35.14 kJ/mol lower than the energy of Polymorph-1, whereas polymorph-2 is stable by 1.21 kJ/mol than Polymorph-3, as shown in Fig. 5, suggesting stability 2 > 3 > 1. These provided the stability gain by the synthons. A recent theoretical study has revealed that a high value of Z׳ (number of symmetry-independent molecules in unit cell) is not reflective of the stability of polymorphs [51]. Our observations suggest that the replica units of the assemblies, as well as the electronic energy of individual molecules, provide the trend of electronic stability of the discrete molecules in different conformations. The optimized energies of assembled structures within assemblies reflect to distinction of their relative gain or loss of stability by forming different synthons. But the total energy gain from dispersive and attractive forces provides insight into the overall stability of the polymorphs. In this case, Polymorph 3 has the lowest energy based on attractive and dispersive energies calculated by CrystalExplorer-17.5 version, and has the highest stability as reflected in the melting temperature. On the other hand, the density of polymorph-3 is lower but it has higher stability.

Differential scanning calorimetry and hot-stage microscopic study

The differential scanning calorimetry (DSC) of the concomitant polymorph was recorded, and it was compared with the DSC of the earlier reported ones. It showed that the Polymorph underwent melting of Polymorph-2 in the mixture at 248°C. Upon further heating, Polymorph-3 melted at 274°C. The first heating and cooling cycle of DSC is shown by the black trace in Fig. 6a. The corroboration of the results with the hot-stage microscopic study showed the melted phase, as shown in the (c) of Fig. 6. Upon cooling after heating up to 300°C, it showed that solidification of the melt at 262°C took place, which, on further cooling, reconverted to an amorphous phase at 221°C corresponding to polymorph-2. The second cycle of heating shown as the red trace of Fig. 6a showed the reversibility of the process, but the solidification at the second cycle took place at 259°C, which was 3°C lower than the first cycle. The images of the cooling samples at two temperatures are shown in Figs. 6b-e. This could be due to defects created within the structures after the first heating cycle, which had affected the colligative properties, affecting the solidification from the melt by forming another form of polymorph. The thermal properties are different from the other two polymorphs. Polymorph-1 melted at 249°C, whereas Polymorph-2 melted at 256°C. While cooling, the Polymorph-1 recrystallized at 233°C, whereas the

Polymorph-2 recrystallized at 253°C [42]. The thermogravimetric analysis shown in Fig. 7S has no weight loss on heating the concomitant polymorphs till 300°C (below this temperature, DSC plots were recorded), but there was a sharp loss of weight at 325°C, where the sample evaporated.

Structural studies on 1-(2,4-dichlorophenyl)-3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)thiourea

We analyzed the structure of DTU from which the Polymorphs were formed, by determing the structure by X-ray single-crystal diffraction. The self-assembled structure of DTU is shown in Fig. 7a. The compound comprises a thiourea part linked to an N-amino 1,8-naphthalimide portion. The packing pattern shows that naphthalimide rings are not stacked but are in a slanted position, with a bisecting angle between the two planes containing such rings was 27.04°, as in (i) of Fig. 7a. Whereas the rings had occupied positions in an intermittent orientation, neither head to tail, nor head to head, as in (ii) of Fig. 7b. Hence, formation of the concomitant polymorph (oppositely having dipoles of the napthalimides) from this assembly will require flipping of one of the rings to reorganize to be parallel with the other and a rotation to make a head-tail orientation as suggested in Fig. 7b. In fact, the same argument would also suggest providing the other

polymorphs from such a decomposition. But the Polymorph-2 and Polymorph-3 had the highest comparable energies. Themogravimetry in Fig. 3S has shown that the compound DTU was stable up to 205°C; hence, polymorphs were formed as a result of a chemical decomposition caused by small amounts of water in the solvent or air that led to the formation of N-amino 1,8-napthalimide from DTU at 80°C. Furthermore, there is a literature example on cyclohexyl-derived thiocarbazide undergoing hydrolytic cleavage to produce a rearranged product [52]. It was also shown that thiocarbazide-based compounds result in different polymorphic solvates by changing crystallization conditions from room temperature to higher temperatures [43]. These observations have suggested that the specific polymorph crystallization was an outcome of the interplay of weak supramolecular interactions during the course of decomposition.

The same synthon but with different symmetry relations provided two independent polymorphs (2 and 3) of N-amino 1,8-naphthalimide that have very close electronic energy differences. These examples have established that hydrogen-bonded chains from crystallographically symmetric molecules or from symmetry-independent molecules provide polymorphs. It is also shown that, while in situ decomposition of the DTU it chooses to crystallise the N-amino,1,8-naphthalimide to adopt a head-to-tail arrangement that is observed in stacks among the molecules of the two concomitant polymorphs. So, having an idea of existing polymorphs, searching for closely related forms is essential, and in this case, success was brought in by serendipity.

Ethics approval, and consent to participate: Not applicable.

Consent for publication: Both authors give consent for the publication of the manuscript in the Journal of BMC Chemistry.

Availability of data and materials: The crystallographic information files of the DUT and Polymorph-3 have the Cambridge Crystallographic Data deposition CCDC numbers 2423507 and 2484027. The supporting materials included with the manuscript are NMR spectra, Thermogravimetry, Crystallographic table, and percentages of contacts from Hirshfeld analysis.

Competing interests: The authors declare that they have no competing interests.

Funding: This research was not part of a sponsored project to the authors; the work was done with support of the Indian Institute of Technology, Guwahati.

Author's contributions: JBB: Conceptualization and writing, theory, and data analysis.

SV: Experiments, Structure determination, data management, and spectral interpretation.

Acknowledgements:

The authors thank the Ministry of Education (India) for providing financial assistance (grant no. F. No. 5-1/2014-TS.VII). The authors also acknowledge the Central Instrumentation Facilities, IIT Guwahati, for instrument facilities. Thanks are due to the Department of Science and Technology, New Delhi, for the use of the SCXRD facility (sanction no. SR/FST/CS-11/2017/23C). Authors also thank Prof. A. Achalkumar for extending help to use the hot-stage microscope and Mr. Sarvar Parvez for recording the higher temperature images of the polymorph.

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Scheme 1 is available in the Supplementary Files section.

No competing interests reported.

SupportingInformation3rdseptember.docx
floatimage1.jpeg
Graphical Abstract
Schem1.png
Scheme 1: The decomposition of DTU leading to N-amino-1,8-naphthalimide.

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You are reading this latest preprint version

Imagination Materializes with Serendipity: Third Polymorph of N-Amino 1,8-Naphthalimide

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Version 1

Abstract

Figures

Introduction

Experimental

General:

Synthesis

Formation of concomitant polymorphs:

Structure determination

Hirshfeld surface analysis

Results and discussions

Structural comparisons among the polymorphs:

Hirshfeld surfaces, total energies and DFT optimized energies:

Differential scanning calorimetry and hot-stage microscopic study

Structural studies on 1-(2,4-dichlorophenyl)-3-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)thiourea

Conclusions

Declarations

References

Scheme 1

Additional Declarations

Supplementary Files

Status:

Version 1