Exploring the Structural Chemistry of Pyrophosphoramides: N N -Tetraisopropylpyrophosphoramide

: N , N (cid:48) , N (cid:48)(cid:48) , N (cid:48)(cid:48)(cid:48) -Tetraisopropylpyrophosphoramide 1 is a pyrophosphoramide with doc-umented butyrylcholinesterase inhibition, a property shared with the more widely studied oc-tamethylphosphoramide (Schradan). Unlike Schradan, 1 is a solid at room temperature making it one of a few known pyrophosphoramide solids. The crystal structure of 1 was determined by single-crystal X-ray diffraction and compared with that of other previously described solid pyrophosphoramides. The pyrophosphoramide discussed in this study was synthesised by reacting iso-propyl amine with pyrophosphoryl tetrachloride under anhydrous conditions. A unique supramolecular motif was observed when compared with previously published pyrophosphoramide structures having two different intermolecular hydrogen bonding synthons. Furthermore, the potential of a wider variety of supramolecular structures in which similar pyrophosphoramides can crystallise was recognised. Proton ( 1 H) and Phosphorus 31 ( 31 P) Nuclear Magnetic Resonance (NMR) spectroscopy, infrared (IR) spectroscopy, mass spectrometry (MS) were carried out to complete the analysis of the compound.


Introduction
N,N ,N ,N -Tetraisopropylpyrophosphoramide 1 (O((iPrNH) 2 PO) 2 ) is a commercially available pyrophosphoramide known to be a butyrylcholinesterase inhibitor [1,2]. Although the molecular structure of the compound is known, crystallographic support for this structure has not been published. Another pyrophosphoramide that has shown cholinesterase inhibition is octamethylpyrophosphoramide (O(Me 2 N) 2 PO) 2 ), which is commonly known as Schradan. This compound, unlike 1, was used as an insecticide for sucking and chewing insects, which are agricultural pests but it has fallen out of use since the 1950's [3,4]. Schradan is a liquid at room temperature making its storage, use, and structural characterisation more problematic than 1. In the mid-twentieth century, apart from its use as a pesticide, Schradan was also studied for its chelation ability with numerous metal centres. These studies mainly dealt with the complexation of Schradan with alkali earth, transition and actinide metals, as well as Sn 4+ [5][6][7][8][9]. Although the complexation ability was proven through numerous analytical methods, including X-ray diffraction (XRD), no industrial or chemical use for these complexes was discussed. Only six other analogues of pyrophosphoramides were found in the literature, namely  [10][11][12][13][14][15]. These solids were characterised by single-crystal X-ray diffraction (SXRD) and published as novel structures with little detailed discussion on any similarities in structure and chemistry as opposed to the research carried out on Schradan. The latter two of the four were compared as part of a Hirshfeld analysis for phosphoramides. O((tBuNH) 2 PO) 2 was complexed with manganese(II) to give the complex [Mn(O(tBuNH) 2 PO) 2 ) 2 DMF 2 ][Cl] 2 · 2H 2 O [16]. This was the only published non-Schradan complex of this group of analogous pyrophosphoramides.
The main objective of this work was to study the supramolecular features of 1 and other, already published, pyrophosphoramides in light of known intermolecular interactions and arrangements [17][18][19][20][21] and to understand their influence on the physical properties of these compounds.

General Considerations
All reactions were carried out under an argon atmosphere using Schlenk line techniques. Chloroform was dried over a P 2 O 5 still, while diethyl ether, THF, petroleum ether and chloroform used in the work-up procedures of the product were dried over 4 Å molecular sieves. FT-IR (Fourier Transform Infrared) spectra were recorded using KBr pellet samples and a Shimadzu IRAffinity-1 FTIR spectrophotometer. 1 H NMR and 31 P NMR (Nuclear Magnetic Resonance) spectra were collected on a Bruker Ascend NMR spectrometer with a probe having a set frequency of 500. 13 MHz for 1 H NMR and 202.457 MHz for 31 P NMR. Gas chromatography Mass spectroscopy (GC MS) data was collected using a Thermo DSQ II GC/MS spectrometer with samples being prepared by dissolution of the products in chloroform. Single-crystal X-ray diffraction data was collected on a STOE STADIVARI diffractometer. The synthesis of O((iPrNH) 2 PO) 2 1 was performed through a modification of the synthesis of the analogous O((Me 2 N) 2 PO) 2 (Schradan) as described by Goehring, M. and Niedenzu, K. in 1956 [22]. Iso-propyl amine (5 mL, 0.058 mol) was dissolved in 10 mL of chloroform as a solvent. The mixture was cooled to −78 • C and pyrophosphoryl tetrachloride (1 mL, 0.007 mol) was added dropwise to the reaction solution using a glass syringe. Upon addition of pyrophosphoryl tetrachloride, the formation of white fumes was noted, along with the formation of a solid crystalline mass. The reaction was left at a temperature of -78 • C until the white fumes dissipated and was subsequently allowed to reach room temperature. The reaction mixture was left to react at room temperature overnight. The white suspension thus formed was subsequently heated to 60 • C for 3 h to complete the reaction. The yellow solution obtained was left overnight to form a clear colourless crystalline mass (iPrNH 3 Cl). The mixture was then filtered to collect a clear colourless crystalline mass (iPrNH 3 Cl) and a yellow solution. The latter was layered with diethyl ether to yield a white solid. Yield, 41% (crude product with respect to pyrophosphoryl tetrachloride), 1  Crystals suitable for SXRD studies were obtained through liquid-liquid diffusion crystallisation: A sample of the white solid product was dissolved in a minimum volume of chloroform to yield a saturated solution. This was layered with 30-40 • C petroleum ether in a 1:5 volume ratio of chloroform/petroleum ether. This produced a liquid-liquid diffusion crystallisation set up which yielded a white crystalline solid over the course of two days. The solid was collected by cannula filtration and crystals suitable for SXRD studies were collected from this solid.

Purification by Column Chromatography
Although single crystals of O((iPrNH) 2 PO) 2 were obtained from the product, it is evident from NMR and GC MS data that this solid was not pure and therefore a sample of O((iPrNH) 2 PO) 2 was also purified by column chromatography to determine whether this was a possible method of purification. The sample was dissolved in dichloromethane and activated Keiselgel 60 was used as the stationary phase, while THF/acetonitrile (1:1 v/v) was used as a mobile phase. 1

Single-Crystal X-ray Diffraction
Crystals were collected under oil and mounted in oil. Data was collected using Cu radiation on a STOE STADIVARI diffractometer, using a 200 K Pilatus detector at 293 K. The ShelXT intrinsic phasing method and ShelXL least squares method were used for structure solution and refinement, respectively (Table 1, Figures 1 and 2). Details regarding the structure solution and refinement procedures are described in Appendix A, while further detailed structural information for this structure is given in Tables S5-S9 in the Supplementary Materials. Crystals were collected under oil and mounted in oil. Data was collected using Cu radiation on a STOE STADIVARI diffractometer, using a 200 K Pilatus detector at 293 K. The ShelXT intrinsic phasing method and ShelXL least squares method were used for structure solution and refinement, respectively (Table 1, Figures 1 and 2). Details regarding the structure solution and refinement procedures are described in Appendix A, while further detailed structural information for this structure is given in Tables S5-S9 in the Supplementary Materials.   2 the hydrogen bonding N3-H1···N2 (blue) and the weak hydrogen bonding observed as C32-H32A···O3 and C41-H41A···O1 (red)(generated using Olex2 [23]); (b) molecular diagram for O((iPrNH) 2 PO) 2 (generated using ChemSketch [24]).

Structural Comparison with Previously Described Pyrophosphoramides
Most intermolecular motifs that build up the supramolecular structure of a compound are due to the moieties within the molecule in question. Therefore, compounds with similar moieties and chemical structures may be expected to have similar intermolecular motifs and in turn, similar crystal structures [17,18]. In this regard, the various pyrophosphoramides discussed in this study can be divided into five main groups, dependent on their chemical structure ( Table 2). On comparison of the crystal structures of the compounds classified in each group, the most important molecular difference that seemed to affect the supramolecular structure was the presence of the N-H moiety. Its presence caused a significant difference between the structure of the mono-N-substituted pyrophosphoramides and the di-N-substituted pyrophosphoramides, which lack this moiety. In the crystal structures of mono-N-substituted pyrophosphoramides P=O···H-N hydrogen bonds were the most prominent and common intermolecular bonds in the structure. These formed numerous intermolecular and intramolecular synthons, which were the primary cause for the formation of the various supramolecular motifs observed, and which dictated both structure and symmetry [17][18][19]. The di-N-substituted pyrophosphoramides were shown to form crystalline structures wherein the pyrophosphoramide moieties did not interact with each other directly. Thus, no strong intermolecular interactions were found. The organic moieties therefore had a significant impact on the packing of molecules in the crystal structures obtained in contrast to the mono-N-substituted pyrophosphoramides (Table 3). Table 3. Hydrogen bond distances in the crystal structure of 1.

D H A d(D-A)/Å d(H-A)/Å d(D-A)/Å D-H-A/
Given that the compound characterised in this current study, 1, was a mono-Nsubstituted pyrophosphoramide its novel structure is best discussed in relation to other mono-N-substituted pyrophosphoramides. Despite its chemical similarities to O((tBuNH) 2 PO) 2 , it not only crystallised in a different spacegroup, namely Pca2 1 , but it also showed a different supramolecular motif. First, the already published structures will be discussed and then compared with 1.
The structures of Mono-N-substituted pyrophosphoramides O((RNH) 2 PO) 2 were found to crystallise in two space groups: either P2 1 /c or Pccn. Common supramolecular arrangements form part of the crystal structures of O((tBuNH) 2 PO) 2 and the two O((2-MePhNH) 2 PO) 2 polymorphs [10][11][12] (Figure 3). The first one is a ring synthon with a R 2 2 (8) graph set binding molecules through intermolecular hydrogen bonding, while in the other [17,19] a partially eclipsed conformations is reached ( Figure 3). The second synthon constricts the molecules from taking on other conformations and therefore minimises the number of possible supramolecular structures available. These two synthons together create the same supramolecular structure for all of the above crystal structures, namely a chain like packing as given in Figure 4. The respective structures for the three mono-Nsubstituted pyrophosphoramides are shown in Figure 5. This structure motif is repeated through translational symmetry to form infinite chains. The two molecules that form the actual supramolecular units are related to each other by the glide plane denoted in the P2 1 /c spacegroup. ry 2021, 3, FOR PEER REVIEW 6 ( ) 8 R 2 2 graph set binding molecules through intermolecular hydrogen bonding, while in the other [17,19] a partially eclipsed conformations is reached ( Figure 3). The second synthon constricts the molecules from taking on other conformations and therefore minimises the number of possible supramolecular structures available. These two synthons together create the same supramolecular structure for all of the above crystal structures, namely a chain like packing as given in Figure 4. The respective structures for the three mono-N-substituted pyrophosphoramides are shown in Figure 5. This structure motif is repeated through translational symmetry to form infinite chains. The two molecules that form the actual supramolecular units are related to each other by the glide plane denoted in the P21/c spacegroup.  graph set binding molecules through intermolecular hydrogen bonding, while in the other [17,19] a partially eclipsed conformations is reached ( Figure 3). The second synthon constricts the molecules from taking on other conformations and therefore minimises the number of possible supramolecular structures available. These two synthons together create the same supramolecular structure for all of the above crystal structures, namely a chain like packing as given in Figure 4. The respective structures for the three mono-N-substituted pyrophosphoramides are shown in Figure 5. This structure motif is repeated through translational symmetry to form infinite chains. The two molecules that form the actual supramolecular units are related to each other by the glide plane denoted in the P21/c spacegroup.  Basic unit for the supramolecular H-bonding motif that is common to all three mono-Nsubstituted pyrophosphoramides crystallising in P2 1 /c (generated using ChemSketch [24]).
Formation of this hydrogen bonding motif seems to be independent of the nature of the organic substituent on the amide nitrogen, as it occurs for both the alkyl tert-butyl and aryl 2-methylphenyl analogues. The packing of these chains is, however, influenced by the organic substituents. The tert-butyl groups in O((tBuNH) 2 PO) 2 pack in a staggered formation resulting in the closest possible packing of the chains [12]. No additional intermolecular interactions are detected within the usual limits.
The packing effects of the 2-methylphenyl groups are more complex than those of the tert-butyl groups. They give rise to two polymorphs of this compound. The two molecular components of these supramolecular units are related to each other by the glide plane imposed by the P2 1 /c spacegroup. In the two O((2-MePhNH) 2 PO) 2 polymorphs however, the direction of the motif is different. The motif in the polymorph reported by Pourayoubi, M. et al. is built along the c axis while the same motif in the polymorph described by Cameron, S.T. et al. is perpendicular to the c axis. Given that the hydrogen bond interaction is identical in both polymorphs, the difference lies in the way the supramolecular chains pack. The polymorph discussed by Pourayoubi et al. [11] showed closer packing between the chains. In both polymorphs the 2-methylphenyl groups are oriented antiparallel to each other (Figures 6 and 7). The stacking distances between the intramolecular 2-methylphenyl moieties are 3.539 Å and 3.933 Å [10,11]. In one polymorph [11] the position of the chains seems mainly influenced by the supramolecular structure given in the diagram shown in Figure 6. A square like motif is formed wherein each side is composed of the Ph(π)···H-C(meta) interactions [17]. Two contact distances of 3.159 Å and 3.188 Å are present, which are shorter than any contact distance reported in the polymorph described by Cameron et al. [10]. The latter forms similar inter-and intramolecular interactions with one much larger contact distances of 4.717 Å and a very oblique interaction between neighbouring molecules, not bound by hydrogen bonding, with a distance of 3.626 Å [10]. The former interaction is longer than any interactions described for the other polymorph and indicates a less efficient packing. Thus, the different modes of packing of the organic moieties are most probably the cause of the formation of the two polymorphs. Formation of this hydrogen bonding motif seems to be independent of the nature of the organic substituent on the amide nitrogen, as it occurs for both the alkyl tert-butyl and aryl 2-methylphenyl analogues. The packing of these chains is, however, influenced by the organic substituents. The tert-butyl groups in O((tBuNH)2PO)2 pack in a staggered formation resulting in the closest possible packing of the chains [12]. No additional intermolecular interactions are detected within the usual limits.
The packing effects of the 2-methylphenyl groups are more complex than those of the tert-butyl groups. They give rise to two polymorphs of this compound. The two molecular components of these supramolecular units are related to each other by the glide plane imposed by the P21/c spacegroup. In the two O((2-MePhNH)2PO)2 polymorphs however, the direction of the motif is different. The motif in the polymorph reported by Pourayoubi, M. et al. is built along the c axis while the same motif in the polymorph described by Cameron, S.T. et al. is perpendicular to the c axis. Given that the hydrogen bond interaction is identical in both polymorphs, the difference lies in the way the supramolecular chains pack. The polymorph discussed by Pourayoubi et al. [11] showed closer packing between the chains. In both polymorphs the 2-methylphenyl groups are oriented antiparallel to each other (Figures 6 and 7). The stacking distances between the intramolecular 2-methylphenyl moieties are 3.539 Å and 3.933 Å [10,11]. In one polymorph [11] the position of the chains seems mainly influenced by the supramolecular structure given in the diagram shown in Figure 6. A square like motif is formed wherein each side is composed of the Ph(π)···H-C(meta) interactions [17]. Two contact distances of 3.159 Å and 3.188 Å are present, which are shorter than any contact distance reported in the polymorph described by Cameron et al. [10]. The latter forms similar inter-and intramolecular      Interestingly, the crystallographic data of the two structures was collected at different temperatures (150K for [11] and 295K for [10,11]). It is, therefore, possible that a polymorphic transition occurs at lower temperatures. This is also in agreement with the difference in the corresponding unit cell volumes.
The mono-N-substituted pyrophosphoramides, which do not crystallise in the P21/c spacegroup, show different inter-and intramolecular hydrogen bonding motifs. Given that the compounds crystallising in the same spacegroup (P21/c) contain both alkyl and aryl moieties and show a different packing of these moieties, a similar observation is ex- was obtained by the reaction of phosphenyl chloride with ortho-methylaniline followed by recrystallisation in methanol. The synthesis of the polymorph obtained by Pourayoubi et al. was not described in the literature to the best of our knowledge. Interestingly, the crystallographic data of the two structures was collected at different temperatures (150 K for [11] and 295 K for [10,11]). It is, therefore, possible that a polymorphic transition occurs at lower temperatures. This is also in agreement with the difference in the corresponding unit cell volumes.
The mono-N-substituted pyrophosphoramides, which do not crystallise in the P2 1 /c spacegroup, show different inter-and intramolecular hydrogen bonding motifs. Given that the compounds crystallising in the same spacegroup (P2 1 /c) contain both alkyl and aryl moieties and show a different packing of these moieties, a similar observation is expected for the 4-methylphenyl and the iso-propyl analogues. However, a different supramolecular structure was formed by the 4-methylphenyl derivative O((4-MePhNH) 2 PO) 2 , crystallising in spacegroup Pccn [13]. There is no intramolecular synthon present (Figure 3b), resulting in a different pattern of supramolecular interactions. The phosphoryl oxygen and the amide nitrogen, which typically form the intramolecular P=O···H-N motif in the P2 1 /c structures, do not show any hydrogen bonding and therefore, the molecules are not limited to an eclipsed conformation (vide supra). They form a staggered conformation that enables the formation of the basic supramolecular building block for this structure. Two molecules are connected via two intermolecular P=O···H-N hydrogen bonds, forming a ring synthon with graph set R 2 2 (12) (Figure 8) [13,19]. Further N-H···Ph and P=O···H-C(Ph(C2)) interactions are observed. The N-H···Ph interactions are formed through the remaining amide moieties which do not interact in the R 2 2 (12) ring described prior and this additional set of interactions seems to stabilise the motif by increasing the packing efficiency and stopping this moiety from forming the previously mentioned intramolecular P=O···H-N bonding. The P=O···H-C(Ph(C2)) interactions also seem to add stability by further aiding the P=O oxygen atoms to obtain the orientation necessary to form this synthon [17,21].
The two molecules are related by a glide plane on the a-c plane along the c axis ( Figure 9) which results in the formation of infinite chains along cell axis c. Neighbouring chains positioned anti-parallel to each other along the b axis and related to each other by a second glide plane along the diagonal of the ab plane. Chains neighbouring each other along the a axis are parallel and again related by translation. The main interaction responsible for arrangement in antiparallel chains is the Ph(π)···H-C(para-methyl) interaction between the closely situated 4-methyphenyl groups bound to different molecules in different chains [21], as noted in Figure 9 [13]. This guarantees the closest possible packing of the various phenyl groups in the molecule. Thus, the 4-methylphenyl groups seem to play a structure forming role in both the formation of a different hydrogen bonding motif and a different packing of the molecules in this structure compared to other pyrophosphoramides. that enables the formation of the basic supramolecular building block for this structure. Two molecules are connected via two intermolecular P=O···H-N hydrogen bonds, forming a ring synthon with graph set ( ) 12 R 2 2 ( Figure 8) [13,19]. Further N-H···Ph and P=O···H-C(Ph(C2)) interactions are observed. The N-H···Ph interactions are formed through the remaining amide moieties which do not interact in the ( ) 12 R 2 2 ring described prior and this additional set of interactions seems to stabilise the motif by increasing the packing efficiency and stopping this moiety from forming the previously mentioned intramolecular P=O···H-N bonding. The P=O···H-C(Ph(C2)) interactions also seem to add stability by further aiding the P=O oxygen atoms to obtain the orientation necessary to form this synthon [17,21]. The ring synthon responsible for the motif given in a simplified diagram (generated using ChemSketch [24]).
The two molecules are related by a glide plane on the a-c plane along the c axis (Figure 9) which results in the formation of infinite chains along cell axis c. Neighbouring chains positioned anti-parallel to each other along the b axis and related to each other by a second glide plane along the diagonal of the ab plane. Chains neighbouring each other along the a axis are parallel and again related by translation. The main interaction responsible for arrangement in antiparallel chains is the Ph(π)···H-C(para-methyl) interaction between the closely situated 4-methyphenyl groups bound to different molecules in different chains [21], as noted in Figure 9 [13]. This guarantees the closest possible packing of the various phenyl groups in the molecule. Thus, the 4-methylphenyl groups seem to play a structure forming role in both the formation of a different hydrogen bonding motif and a different packing of the molecules in this structure compared to other pyrophosphoramides.  [25]); (b) The ring synthon responsible for the motif given in a simplified diagram (generated using ChemSketch [24]). The 2-methylphenyl and 4-methylphenyl derivatives both crystallise in different supramolecular structures and space groups. However, the 2-methylphenyl pyrophosphoramide crystallises in the same space group and shows the same supramolecular bonding as that for the tert-butyl analogue. O((4-MePhNH)2PO)2. The latter was collected at 90 K, whereas the O((2-MePhNH)2PO)2 polymorphs were collected at 150 K and 295 K [10,11,13]. Thus, it is unclear whether the occurrence of different structural motifs is mainly caused by the different nature of the side groups or simply because the single crystal data was collected for each compound at different temperatures No intramolecular P=O···H-N hydrogen bonding is present in the crystal structure of 1. This leads to the formation of a staggered arrangement of the pyrophosphoramide group similar to that observed for O((4-MePhNH)2PO)2. Thus again, the lack of intramolecular bonding between amide and phosphoroxide seems to hinder an eclipsed conformation (vide supra, Figure 3b) and related supramolecular motifs. The most important supramolecular motif in the structure of 1 is therefore the P=O···H-N interaction. This is in agreement with what was observed also in all other mono-N-substituted pyrophosphoramides, where intermolecular hydrogen bonding was a major factor in the formation of the relevant supramolecular motifs [10][11][12][13]. The actual synthon is shown in Figure 10. It is formed by two molecules of 1 related to each other by translation symmetry via two different P=O···H-N hydrogen bonding synthons. To the best of our knowledge this is the The 2-methylphenyl and 4-methylphenyl derivatives both crystallise in different supramolecular structures and space groups. However, the 2-methylphenyl pyrophosphoramide crystallises in the same space group and shows the same supramolecular bonding as that for the tert-butyl analogue. O((4-MePhNH) 2 PO) 2 . The latter was collected at 90 K, whereas the O((2-MePhNH) 2 PO) 2 polymorphs were collected at 150 K and 295 K [10,11,13]. Thus, it is unclear whether the occurrence of different structural motifs is mainly caused by the different nature of the side groups or simply because the single crystal data was collected for each compound at different temperatures No intramolecular P=O···H-N hydrogen bonding is present in the crystal structure of 1. This leads to the formation of a staggered arrangement of the pyrophosphoramide group similar to that observed for O((4-MePhNH) 2 PO) 2 . Thus again, the lack of intramolecular bonding between amide and phosphoroxide seems to hinder an eclipsed conformation (vide supra, Figure 3b) and related supramolecular motifs. The most important supramolecular motif in the structure of 1 is therefore the P=O···H-N interaction. This is in agreement with what was observed also in all other mono-N-substituted pyrophosphoramides, where intermolecular hydrogen bonding was a major factor in the formation of the relevant supramolecular motifs [10][11][12][13]. The actual synthon is shown in Figure 10. It is formed by two molecules of 1 related to each other by translation symmetry via two different P=O···H-N hydrogen bonding synthons. To the best of our knowledge this is the only mono-N-substituted pyrophosphoramide structure to exhibit multiple intermolecular hydrogen bonding synthons. The first synthon is a ring with a R 1 2 (8) graph set connecting one P=O group with two neighbouring N-H groups, which are bound to the two different phosphorus centres of the second molecule. The second synthon consists of a P=O···H-N interaction between the other P=O group of the first molecule and a neighbouring N-H group. The latter is not part of the previously discussed synthon; it shares, however, a phosphorus centre with one of the previously discussed amide groups. Neighbouring chains along the a axis pack anti-parallel to each other via a 2 1 screw axis ( Figure 11). The remaining amide does not seem to participate in any type of intermolecular or intramolecular bonding, even though, theoretically, infinite chains along the b axis could be formed in a similar manner as observed in other mono-N-substituted pyrophosphoramides (vide supra). Therefore, the main mode of intermolecular interactions is the Van der Waals forces that caused the hydrophobic iso-propyl groups to stack.  The cause for the formation of this different supramolecular motif is difficult to determine as the different molecular structure, synthesis, crystallisation techniques, and solvents used can all affect crystallization process and lead to this crystal structure. The temperature at which single crystal data was obtained is unlikely to be the cause of this as it falls into the same range as for the other compounds crystallising in spacegroup P21/c [10][11][12]. The synthesis and crystallisation approach used to obtain single crystals of 1 differs from published procedures to obtain crystalline material for the related compounds. Given the chemical similarities between the iso-propyl and tert-butyl moiety the differ- Figure 10. Hydrogen bonding synthons present in the structure of O((iPrNH) 2 PO) 2 (generated in Mercury [25] and ChemSketch [24]).  The cause for the formation of this different supramolecular motif is difficult to determine as the different molecular structure, synthesis, crystallisation techniques, and solvents used can all affect crystallization process and lead to this crystal structure. The temperature at which single crystal data was obtained is unlikely to be the cause of this as it falls into the same range as for the other compounds crystallising in spacegroup P21/c [10][11][12]. The synthesis and crystallisation approach used to obtain single crystals of 1 differs from published procedures to obtain crystalline material for the related compounds. Given the chemical similarities between the iso-propyl and tert-butyl moiety the differ- Figure 11. Antiparallel chains of O((iPrNH) 2 PO) 2 noted along the a-axis (generated in Mercury [25]).
The cause for the formation of this different supramolecular motif is difficult to determine as the different molecular structure, synthesis, crystallisation techniques, and solvents used can all affect crystallization process and lead to this crystal structure. The temperature at which single crystal data was obtained is unlikely to be the cause of this as it falls into the same range as for the other compounds crystallising in spacegroup P2 1 /c [10][11][12]. The synthesis and crystallisation approach used to obtain single crystals of 1 differs from published procedures to obtain crystalline material for the related compounds. Given the chemical similarities between the iso-propyl and tert-butyl moiety the difference in supramolecular motifs between the two is unexpected.  [13][14][15]. No significant classical intermolecular interactions between the pyrophosphoramide or organic moieties are present in the corresponding published crystal structures. The pyrophosphoramide backbone forms a similar staggered conformation in all three compounds. In O((BzMeN) 2 PO) 2 , the main intermolecular interactions effecting the supramolecular structure are weak C-H···Ph interactions [13]. These form in two different synthons, namely N-Me···Ph(C2) and CH 2 (benzyl)···Ph. The molecules pack in layers linked along the axis c ( Figure 12) [17,21]. The crystal structure of O((C2H4(2,5-iPrPhN)2)2PO)2 shows only very weak intermolecular interactions [14]. The pyrophosphoramide moieties seem to be isolated from each other by the bulky hydrophobic organic moieties ( Figure 13).  [25]); (b) simplified diagram of the supramolecular motif (generated using ChemSketch [24]).
In the crystal structure of O((1,2-Cy(NaphN) 2 ) 2 PO) 2 intermolecular motifs (C-H···Ph interactions) are present similar to those observed in the structure of O((BzMeN) 2 PO) 2 . Intermolecular interactions are noted between the benzyl methylene, the naphthyl groups and the cyclohexyl -CH 2 -groups. Three distinct C-H···Ph interactions are present namely CH 2 (benzyl methylene)···naphthyl(C4), C-H(Naphthyl(C8))···naphthyl(C10), and CH 2 (cyclohexyl)···napthyl(C3) [15]. These interactions are unidirectional, with the proton donors binding to the closest naphthalene along the c axis, which is typically the molecule diagonal to the proton donor molecule in the layers running along axis a (Figure 14). The pyrophosphoramide group is connected to hydrate water by hydrogen bonding forming a R 2 2 (8) ring [15]. This ring motif separates the pyrophosphoramide molecule structurally from any further interaction with typical hydrogen bonding electron acceptors.
The crystal structure of O((C2H4(2,5-iPrPhN)2)2PO)2 shows only very weak intermolecular interactions [14]. The pyrophosphoramide moieties seem to be isolated from each other by the bulky hydrophobic organic moieties ( Figure 13).   CH2(benzyl methylene)···naphthyl(C4), C-H(Naphthyl(C8))···naphthyl(C10), and CH2(cyclohexyl)···napthyl(C3) [15]. These interactions are unidirectional, with the proton donors binding to the closest naphthalene along the c axis, which is typically the molecule diagonal to the proton donor molecule in the layers running along axis a ( Figure 14). The pyrophosphoramide group is connected to hydrate water by hydrogen bonding forming a ( ) 8 R 2 2 ring [15]. This ring motif separates the pyrophosphoramide molecule structurally from any further interaction with typical hydrogen bonding electron acceptors. In all three cases the supramolecular structure is dominated by the organic substituents. There is complete lack of π-π stacking interactions. A possible reason for this might be that the pyrophosphoramide backbone always takes on a more staggered conformation forcing the organic substituents into unfavorable positions to form π-π stacking. The staggered conformation itself is most likely caused by the lack of the amine N-H bonds, which usually force the molecule in a more eclipsed conformation through inter/intramolecular bonding as observed in some of the mono-N-substituted pyrophosphoramides.

Conclusions
The crystal structure of the mono-N-substituted pyrophosphoramide, O((iPrNH)2PO)2 1 has been determined from single-crystal X-ray diffraction data while the chemical identity of the species was supported by IR, 1 H NMR, 31 P NMR, and GC MS data (see SI). A thorough structural comparison of 1 with other pyrophosphoramides for which the crystal structures have been published previously was carried out. 1 forms a novel supramolecular motif previously unattested for mono-N-substituted pyrophosphoramides. This motif was composed of two different synthons with P=O···H-N interactions. The great impact of this type of hydrogen bonding on the supramolecular motifs in all previously published mono-N-substituted pyrophosphoramides could be confirmed also for 1. Trends regarding the effects of the various organic moieties within the different compounds were difficult to describe due to the lack of systematic data. No comparison of 1 with the di-N-substituted pyrophosphoramides was undertaken, given that the trends In all three cases the supramolecular structure is dominated by the organic substituents. There is complete lack of π-π stacking interactions. A possible reason for this might be that the pyrophosphoramide backbone always takes on a more staggered conformation forcing the organic substituents into unfavorable positions to form π-π stacking. The staggered conformation itself is most likely caused by the lack of the amine N-H bonds, which usually force the molecule in a more eclipsed conformation through inter/intramolecular bonding as observed in some of the mono-N-substituted pyrophosphoramides.

Conclusions
The crystal structure of the mono-N-substituted pyrophosphoramide, O((iPrNH) 2 PO) 2 1 has been determined from single-crystal X-ray diffraction data while the chemical identity of the species was supported by IR, 1 H NMR, 31 P NMR, and GC MS data (see SI). A thorough structural comparison of 1 with other pyrophosphoramides for which the crystal structures have been published previously was carried out. 1 forms a novel supramolecular motif previously unattested for mono-N-substituted pyrophosphoramides. This motif was composed of two different synthons with P=O···H-N interactions. The great impact of this type of hydrogen bonding on the supramolecular motifs in all previously published mono-N-substituted pyrophosphoramides could be confirmed also for 1. Trends regarding the effects of the various organic moieties within the different compounds were difficult to describe due to the lack of systematic data. No comparison of 1 with the di-N-substituted pyrophosphoramides was undertaken, given that the trends in packing are significantly different between this group and the mono-N-substituted pyrophosphoramides.
The differences observed between the supramolecular motifs present in 1 and the supramolecular features of other mono-N-substituted pyrophosphoramides indicate that there are possibly other supramolecular motifs that have not yet been discovered yet. The crystal structure of 1 further expands the diversity of possible supramolecular synthons. The different synthon in 1 (R 1 2 (8)ring), not known in previously described mono-N-substituted pyrophosphoramides, adds a new strong structural motif to the viable synthons known experimentally for mono-N-substituted pyrophosphoramides. It can also be considered to be a viable option for the discovery of new co-crystals of these species [20,21]. Different solid-state forms of pyrophosphoramides as well as co-crystals formed with other organic and inorganic species will have different physical properties and, at times different chemical properties compared to the currently marketed compounds without changing the actual molecule [26][27][28][29][30]. This is important for mono-N-substituted pyrophosphoramides given their possible use as a pesticide. The formation of different forms with different thermodynamic and kinetic stabilities can aid in complexation reactions and e.g., diminish decomposition on storage, a property of great importance for use in agriculture [28,29,31,32].
However, given the disparity between the various experimental techniques used in both the structures described in the literature and the current study further work at different temperatures, including X-ray data from powders, must be undertaken to obtain a more comprehensive understanding of the relationship between the chemical and physical properties and the crystal structures of various pyrophosphoramides.

Data Availability Statement:
The data presented in this study are available in the supplementary materials.