Diastereotopic groups in two new single-enantiomer structures (R 2)P(O)[NH-(+)CH(C2H5)(C6H5)] (R = OC6H5 and C6H5)

Two new single-enantiomer phosphorus structures were studied. Their geometries, conformations and NMR features are discussed.


Chemical context
Phosphoramide/phosphinamide moieties are well-known structural motifs of some bioactive products and drugs (Warren et al., 2016;Palacios et al., 2005).There are also reports on their applications in flame retardants (Nguyen & Kim, 2008), ligands (Wang et al., 2021;Ferentinos et al., 2019;Zhang et al., 2019), extractants (Akbari et al., 2019), anion transporters (Cranwell et al., 2013) and catalysts (Klare et al., 2014).Some of these characteristics are general for phosphoramide/phosphinamide compounds, and can be influenced by the groups attached to the common NP O unit.Typically, the donor property of the phosphoryl group is beneficial in sorption processes, interactions with some enzymes and the formation of hydrogen bonds (Corbridge, 2000).The subfamily to which the compounds belong also plays a role.For example, phosphinicamides with the (C) 2 P(O)(N) skeleton are found to have higher electron-donor properties with respect to amidophosphodiesters with the (O) 2 P(O)(N) skeleton.The chirality may also be essential for some particular applications, such as the manufacture of drugs and the planning of some reactions related to different reactivities of diastereotopic groups (Nakayama & Thompson, 1990), enantioseparation (Ahmadabad et al., 2019) and enantioselective catalysis (Liao et al., 2019).
Recently, we have reported some single-enantiomer small molecules, belonging to the phosphoramide family, and phosphoramide-based macromolecules/hydrogels (Ahmadabad et al., 2019;Taherzadeh et al., 2021;Sabbaghi et al., 2019).The related synthesis procedure could also be developed for manufacturing phosphinamide-based materials.Moreover, we are interested in studying the differences between two diastereotopic groups in chiral structures.The reason for such attention is the asymmetric induction at phosphorus by the chiral group, which causes different reactivities of two diastereotopic groups (Nakayama & Thompson, 1990).These differences were investigated in organic syntheses for the creation of new stereocentres and also can be used for the design and synthesis of ligands with different donor properties of the diastereotopic groups.
In the present work, we continue with the synthesis of new chiral (C 6 H 5 O) 2 P(O)[NH-(+)CH(C 2 H 5 )(C 6 H 5 )] phosphoramide, (I), and (C 6 H 5 ) 2 P(O)[NH-(+)CH(C 2 H 5 )(C 6 H 5 )] phosphinamide, (II) to study structural differences of two diastereotopic C 6 H 5 O/C 6 H 5 groups, caused by the same chiral amine.Structure I is the enantiomer of the previously reported (C 6 H 5 O) 2 P(O) [NH-(-)CH(C 2 H 5 )(C 6 H 5 )] (Sabbaghi et al., 2011).The investigation is completed by considering structural differences/similarities of diastereotopic groups in analogous chiral structures retrieved from the CSD (Groom et al., 2016).The main features of the NMR parameters of the diastereotopic groups in I and II are also discussed.

Structural commentary
Compound I crystallizes in the orthorhombic chiral space group P2 1 2 1 2 1 , with the asymmetric unit composed of one amidophosphodiester molecule (Fig. 1).Compound II is triclinic in chiral space group P1, and its asymmetric unit consists of two phosphinicamide molecules (Fig. 2).Selected bond lengths and angles are presented in Tables 1 and 2. All bond distances and angles are within the values observed in analogous structures (Vahdani Alviri et al., 2020;Hamzehee et al., 2017).
The P atoms display a distorted tetrahedral environment, (O) 2 P(O)(N) for I and (C) 2 P(O)(N) for II, and the maximum/ minimum bond angles at phosphorus are related to O P-O/ O-P-O and O P-N/N-P-C.The differences between maximum and minimum values are about 16.8 for I and 17.5 / 16.9 for the two symmetry-independent molecules of II.The P-N-C angles in I and II, for example, P1-N3-C4 angle in II of 120.91 (14) (Table 2), demonstrate that the hybridization state of nitrogen atoms is close to sp 2 .The P-O-C angles of I, 127.68 (17) /121.91 (16) , similarly show the hybridization state of the ester oxygen atoms is close to sp 2 .
The structure I is similar to its S-enantiomer (EXIQIM; Sabbaghi et al., 2011) regarding space group, unit cell and other structural parameters; the only substantial difference is related to the configuration at dissymmetric carbon atoms.The asymmetric unit of I, showing the atom-numbering scheme for nonhydrogen atoms and displacement ellipsoids at 50% probability level.Hydrogen atoms are drawn as spheres of arbitrary radii.The longer P-N bond in II is also caused by the steric effects of two phenyl groups directly attached to phosphorus.Minor differences are observed for the bond lengths related to the diastereotopic pairs.Typically, the P-O and P-C bonds in I and two independent molecules of II are 1.581 (2)/1.592(2) A ˚, 1.802 (2)/1.808(2) A ˚and 1.808 (2)/1.797(2) A ˚.In compound I, the N-H unit adopts an antiperiplanar (-ap) orientation with respect to the P O group (based on the O P-N-H torsion angle of À157.18 ), and in two symmetry-independent molecules of II, the same units adopt synclinal (-sc and +sc) conformations (the torsion angles are À80.63 and +84.78 ).The different conformation of II (in comparison to I) results from intramolecular rotations of the chiral amine, and the two independent molecules feature different rotations, but with a similar O P-N-H conformation.
In II, the symmetry-independent molecules are similar concerning the bond lengths and angles (see Table 2).However, they show some differences in torsion angles (and conformations).Typically, the conformations in the CH 3 -CH 2 -CH-NH-P O segment are defined by the C-C-C-N/C-C-N-P/C-N-P O torsion angles, and the values in the P1 molecule of +173.7 (2) /À98.2 (2) /60.7 (2) correspond to +ap/Àac/+sc conformations (ac = anticlinal).Similar torsion angles in the other molecule, À178.3 (2) / À158.6 (2) /À62.0 (2) , define Àap/-ap/Àsc conformations.The other notable difference between the two molecules is reflected in the direction of the phenyl ring of the chiral segment with respect to the P O group (an opposite direction in the molecule P1 and the same direction in the second molecule).Fig. 3b shows the overlay of two molecules, and the root-mean-square deviation (r.m.s.d.) of the fit of them is 1.3533A ˚with a maximum deviation of 4.6684 A ˚.The noted difference is reflected in the spatial distances of phenyl groups bonded to P and the phenyl group of chiral amine in the two molecules.The differences in diastereotopic phenyl rings in each molecule can also be described by their distances from the phenyl ring of the chiral amine.
For I, the distances between the centroid of the phenyl ring of chiral amine and the centroids of two diastereotopic phenyl groups are 5.0848 (1) and 7.9514 (1) A ˚.For the two symmetryindependent molecules of II, equivalent distances are 5.5767 (5)/7.0325(6) A ˚and 7.1614 (6)/6.4951(3) A ˚.These spatial distances show that one of the diastereotopic phenyl rings is significantly closer to the phenyl of the chiral amine.The differences in these spatial distances are pronounced in I, where the flexibility is greater (because of the existence of the P-O-C segment and the possibility of rotation).

Supramolecular features
In the crystal structures of I and II, the molecules are assembled in a chain arrangement through N-HÁ Á ÁO(P) hydrogen bonds along [100] (Fig. 4, Tables 3 and 4).The N-HÁ Á ÁO(P) hydrogen bond in I is weaker than in II (HÁ Á ÁO distances are 2.24 and 1.97/2.08A ˚, respectively).This weakness is the result of the lower hydrogen-bond acceptor capability expected for the phosphoryl group of an    symmetry-related magenta ring (HÁ Á ÁCg = 3.23 A ˚) and also in a C-HÁ Á ÁOP interaction (HÁ Á ÁO = 2.55 A ˚).The formed twodimensional assembly is double-layered and has a thickness of 18.057A ˚in the c-axis direction.
In the structure of II, two possible C-HÁ Á Á interactions exist (HÁ Á ÁCg distances of 3.41 and 3.49 A ˚), which do not change the dimensionality made by the N-HÁ Á ÁO hydrogen bonds.In both C-HÁ Á Á interactions, the H donors are chiral amines of two symmetry-independent molecules (the orthohydrogen atom and the hydrogen of the CH 2 unit, as shown in Fig. 6).The acceptors are one of the diastereotopic phenyl rings of the molecule including atom P1 and the phenyl ring of the chiral amine in the other molecule.

An overview of diastereotopic groups in analogous structures
The chiral structures with an  S1 of the supporting information.The largest difference for the P-C bond lengths made by diastereotopic groups (0.025 A ˚) exceeds the largest differences for the P-O (0.017 A ˚) and P-N bond lengths (0.015 A ˚).The P-C, P-N and P-O bond lengths in these structures vary from 1.773 to 1.837 A ˚, 1.629 to 1.652 A ˚and 1.555 to 1.607 A ˚, respectively, with averages of 1.805, 1.643 and 1.580A ˚.The conformations of diastereotopic groups attached to phosphorus were analysed in the structures analogous to I and II, i.e. with the O 2 P and C 2 P skeletons.Only three O 2 P-based structures (with the oxygen atom attached to an arene ring) were found in the CSD.For the C 2 P skeleton, 36 structures, including 64 R 2 PX fragments, were checked, and the C-C-P X (X = O, N, S) torsion angles were evaluated.
The C 2 P-based structures mainly include Ph 2 P(O) fragment (28 structures), similar to compound II; however, structures with Ph 2 P(S) (seven structures), and (C 6 H 11 ) 2 P( N) (one structure) fragments were also found.Both similar and different conformations were observed for diastereotopic groups.Details of the analysis are given in Table S2 and Fig. S1 of the supporting information.The torsion angles such as C-C-P O of 0.04 in the structure with refcode MEFCIK (Sweeney et al., 2006) show the P O group nearly in a plane where the phenyl ring also exists.Its complementary torsion angle for the other C-C-P O related to this phenyl ring is 176.54 , and these two torsion angles define the sp+ap conformation of this phenyl ring with respect to the P O group.On the other hand, most of the structures also include AEspAEap conformations at least for one phenyl ring.The most populated conformations for diastereotopic fragments (separated by "/") are AEspAEap/AEspAEap (26 entries) and AEspAEap/ AEscAEac (23 entries).In the systems with phenyl rings directly attached to the phosphorus atom, as a result of crowding, the simultaneous torsion angles around AE90 (a perpendicular conformation) for both phenyl rings were not found for any structure.In some cases, like in the structure with refcode VUGSOG (Yin et al., 2009) with close phenyl rings, the CH unit of one phenyl ring is directed toward the centroid of the second phenyl ring because of the formation of an intramolecular C-HÁ Á Á interaction.
As a result of the existence of C-O-P moiety in the O 2 Pbased structures, the flexibility is expected to be higher than for Ph 2 P-based structures; the three structures show different conformations but they include AEscAEac conformations at least in one arene ring.

Hirshfeld surface analyses and fingerprint plots of structures I and II
To visualize and compare the intermolecular contacts of I and II, the Hirshfeld surfaces (HS) mapped with d norm and twodimensional fingerprint plots (Spackman & Jayatilaka, 2009;Spackman et al., 2021) were generated using the Crystal-Explorer program (Wolff et al., 2013).In the HS map of I (Fig. 7), the red areas are associated with the N-HÁ Á ÁO, C-HÁ Á ÁO and 2ÂC-HÁ Á Á interactions [labels (i), (ii) and (iii)].The contacts of I, obtained from the fingerprint plots, are HÁ Á ÁH (57.3%),HÁ Á ÁC (28.8%),HÁ Á ÁO (12.7%) and OÁ Á ÁC (1.2%).The OÁ Á ÁC contact results from the near distance of two symmetry-related phenoxy groups [O2(C3-C8)], through the ester oxygen atom and -system.For II, the HS map was generated around two symmetryindependent molecules step by step.Besides N-HÁ Á ÁO hydrogen bonds, a significant HÁ Á ÁH contact develops a red area, as seen in Fig. 8.This interaction is between H231 of the phenyl ring of molecule P1 connected to H301 of the chiral amine of the other molecule.The HÁ Á ÁH separation was obtained as 2.291 A ˚and 2.026 A ˚in the X-ray and Hirshfeld analyses, respectively (the neutron-normalized CH distance is 1.083A ˚in Hirshfeld in comparison with 0.941/0.943A ˚in X-ray).

Spectroscopy of I and II
In the IR spectra, the N-H stretching bands are centred at 3268 cm À1 for I and 3152 cm À1 for II.The lower NH stretching wave number of II is attributed to stronger N-HÁ Á ÁOP hydrogen bonds as discussed in the X-ray crystallography section.The bands at 1244 cm À1 for I and 1192 cm À1 for II are assigned to the P O vibrations, and the higher wave number for I is in accordance with the presence of more electro- For the two diastereotopic C 6 H 5 O groups in I, two sets of carbon signals are observed.For example, the doublets at 150.74/150.92p.p.m. and 120.12/120.23 p.p.m., with 2 J = 7.0 Hz for the first pair and 3 J = 4.0 Hz for the second pair, are associated with the diastereotopic ipso-C atoms and diastereotopic ortho-C atoms, respectively.All carbon atoms of diastereotopic phenyl groups in compound II show couplings with phosphorus ( 1 J, 2 J, 3 J and 4 J).
The A brief discussion of 31 P NMR and 1 H NMR spectroscopy is given in the supporting information (Figures S2 to S11).

Conclusions
The differences/similarities of diastereotopic pairs,  differences are related to the contributions in the crystal packing by diastereotopic groups, especially in the C-HÁ Á Á interactions, and the NMR chemical shifts of corresponding 13 C signals.The geometry parameters, conformations and NMR coupling constants of diastereotopic groups show minor differences (and/or similarities in some cases).In I with the O 2 P(O)N skeleton, the shorter P O/P-N bonds and weaker N-HÁ Á ÁO P hydrogen bond are observed with respect to the structure II with the C 2 P(O)N skeleton.These structural features, resulting from different electronegativities of atoms, are reflected in the higher stretching frequencies of P O and N-H bonds in the structure I (the latter because of a weaker N-HÁ Á ÁO P hydrogen bond).The lower volume/Z ratio of II is reflected by the crowding and observation of CÁ Á ÁC contacts and raising HÁ Á ÁH contacts, while I includes more HÁ Á ÁO and OÁ Á ÁC contacts.The study of analogous chiral structures retrieved from the CSD shows minor differences in bond lengths for diastereotopic P-C, P-O, and P-N bonds and more significant differences in torsion angles of diastereotopic groups.

Synthesis and crystallization
To a solution of (C 6 H 5 O) 2 P(O)Cl in dry chloroform, a solution of R-(+)-1-phenylpropylamine and triethyl-amine (1:1:1 molar ratio) in the same solvent was added at 273 K.After stirring for 4 h, the solvent was removed in a vacuum, and the obtained solid was washed with distilled water to remove (C 2 H 5 ) 3 NHCl.Colourless crystals were obtained from a solution of the title compound in CHCl 3 / CH 3 CN (1:2 v/v) after slow evaporation at room temperature.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 5.The H atoms were all located in difference-Fourier maps, but those attached to C atoms were repositioned geometrically.The H atoms were initially refined with soft restraints on the bond lengths and angles to regularize their geometries (C-H in the range 0.93-0.98A ˚, N-H in the range 0.86-0.89A ˚) and U iso (H) values in the range 1.2-1.5ÂUeq of the parent atom, after which the positions were refined with riding constraints (Cooper et al., 2010;Watkin & Cooper, 2016).The absolute configuration was determined from the refinement of the Flack parameter (Parsons et al., 2013).Refinement.X-ray analyses of I and II were performed on two different diffractometers, both using mirror-collimated Cu-Kα radiation (λ = 1.5418Å), and CCD detector Atlas S2.The 120 K data set was acquired on a Gemini diffractometer with a classical sealed X-ray tube, while the 95 K data set was obtained on a SuperNova diffractometer with a microfocus sealed tube.The data reduction and absorption correction were made with CrysAlis PRO software (Rigaku, 2017).The structures were solved by charge flipping methods using SUPERFLIP (Palatinus & Chapuis, 2007) software and refined by full-matrix least-squares on F squared value using Crystals (Betteridge et al., 2003)   Hydrogen-bond geometry (Å, º)

Figure 2
Figure 2Displacement ellipsoid plot (50% probability) of the asymmetric unit of II, showing the atom-numbering scheme for non-hydrogen atoms.Hydrogen atoms are drawn as spheres of arbitrary radii.

Figure 3 (
Figure 3 (a) Overlay of EXIQIM (grey) and inverted I (blue).(b) Overlay of two symmetry-independent molecules of II (green and blue show molecules P1 and P25, respectively).

Figure 4
Figure 4 Crystal packing of I (top) and II (bottom).The red, orange, light-blue and pink balls show oxygen, phosphorus, nitrogen and hydrogen attached to nitrogen atoms.For I, carbon atoms and attached hydrogen atoms are shown in light green.For II, two-symmetry independent molecules are shown in light green and blue.The dotted lines show N-HÁ Á ÁO hydrogen bonds.

Figure 5 A
Figure 5 A view of the two-dimensional double-layered arrangement of I formed by N-HÁ Á ÁO, C-HÁ Á ÁO and C-HÁ Á Á interactions (shown as black, blue and red dotted lines, respectively).The centroids of the phenyl rings taking part as acceptors in C-HÁ Á Á interactions are shown as balls of the same colours as the corresponding ring.
were retrieved from the CSD to study possible structural differences for diastereotopic R groups; the metal complexes were not considered.The CSD (version 5.42 updated on Feb. 2021; Groom et al., 2016) comprises 48 such structures, of which two were unavailable.The remaining 46 structures include 79 pairs of diastereotopic P-Y (Y = C, O, N) bonds, and the structures have different skeletons, (C) 2 P(O)(N), (C) 2 P(S)(N), (C) 2 P(N)(N), (O) 2 P(O)(N) and (N) 2 P(O)(N).The related bond lengths are given in Table

Figure 6 A
Figure 6 A view of the one-dimensional arrangement of structure II formed by N-HÁ Á ÁO and C-HÁ Á Á interactions (shown as black and red dotted lines).Only the hydrogen atoms participating in these hydrogen-bond interactions are shown.
negative atoms in the (O) 2 P(O)N skeleton [versus (C) 2 P(O)N for II].In the 13 C NMR spectra, the doublet signals at 31.80 p.p.m. ( 3 J = 8.1 Hz) for I and at 32.62 p.p.m. ( 3 J = 4.7 Hz) for II correspond to the CH 2 group.The dissymmetric carbon atom does not show coupling with phosphorus, and the ipso-C atom attached to it, i.e. with a three-bond separation from phosphorus, shows a doublet at 143.04 p.p.m. ( 3 J = 3.0 Hz) in I and at 145.50 p.p.m. ( 3 J = 4.6 Hz) in II.
Figure 8Hirshfeld surface map generated step by step around two symmetryindependent molecules of II.The two molecules outside the surface were given to show the hydrogen-bond interactions with the molecules within the surface.The red region labelled (i) is related to a close HÁ Á ÁH contact between the molecules within and outside the surface (not shown).

Figure 7
Figure 7 Hirshfeld surface map generated for the structure I. Two molecules are shown outside the surface to represent the N-HÁ Á ÁO [label (i)], C-HÁ Á ÁO [label (ii)] and typical C-HÁ Á Á [label (iii)] interactions with the molecule within the surface.

Table 1
Selected geometric parameters (A ˚, ) for I.

Table 2
Selected geometric parameters (A ˚, ) for II.

Table 3
Hydrogen-bond geometry (A ˚, ) for I.

Table 5
Experimental details.