Two Modifications of Nitrilotris(methylenephenylphosphinic) Acid: A Polymeric Network with Intermolecular (O=P–O–H) 3 vs. Monomeric Molecules with Intramolecular (O=P–O–H) 3 Hydrogen Bond Cyclotrimers

: Nitrilotris(methylenephenylphosphinic) acid ( NTPAH 3 ) was silylated using hexamethyldis-ilazane to produce the tris(trimethylsilyl) derivative NTPA(SiMe 3 ) 3 . From the latter, upon alcoholysis in chloroform, NTPAH 3 could be recovered. Thus, a new modification of that phosphinic acid formed. Meanwhile, NTPAH 3 synthesized in aqueous hydrochloric acid crystallized in the space group P 3 c 1 with the formation of O-H ··· O H-bonded networks ( NTPAH 3P ), in chloroform crystals in the space group R 3 c formed ( NTPAH 3M ), the constituents of which are individual molecules with exclusively intramolecular O-H ··· O hydrogen bonds. Both solids, NTPAH 3P and NTPAH 3M , were characterized by single-crystal X-ray diffraction, multi-nuclear ( 1 H, 13 C, 31 P) solid-state NMR spectroscopy, and IR spectroscopy as well as quantum chemical calculations (both of their individual constituents as isolated molecules as well as in the periodic crystal environment). In spite of the different stabilities of their constituting molecular conformers, the different crystal packing interactions rendered the modifications of NTPAH 3P and NTPAH 3M similarly stable. In both solids, the protons of the acid are engaged in cyclic (O=P–O–H) 3 H-bond trimers. Thus, the trialkylamine N atom of this compound is not protonated. IR and 1 H NMR spectroscopy of these solids indicated stronger H-bonds in the (O=P–O–H) 3 H-bond trimers of NTPAH 3M over those in NTPAH 3P .


Introduction
Nitrilotris(methylenephosphinic) acids are essentially related to nitrilotris(acetic) acid I (Figure 1), which has been shown to crystallize as a zwitterionic compound [1,2].The protonation of the α-amine N atom by one of the acidic groups is a common feature, which is very well known from biogenic α-amino acids [3].Upon replacing carboxylic with phosphinic (compound II, [4]) or phosphonic acid groups (compound III [5]), the slightly more acidic P-containing acid groups (for example, PhMePOOH [6] and arylphosphinic acids of the type Aryl(H)POOH [7] were shown to be more acidic than benzoic acid) serve as protonators, and this is also true for nitrilotris(methylenephosphonic) acid IV [8] and compound V [9].In contrast to the double-zwitterionic nature of V, cyclohexane-1,2diamine derivative VI [10] has mono-zwitterionic features.The lone pair of its second N atom is involved in an N-H•••N hydrogen bond and thus less susceptible to protonation.In previous studies [11,12] nitrilotris(methylenephenylphosphinic) acid (NTPAH3) was shown to be an interesting tripodal ligand.In the course of our ongoing investigations of Si-O-P compounds [13][14][15], phosphinic acids revealed interesting coordination features at silicon [16].In this context, we prepared both NTPAH3 and its trimethylsilyl derivative NTPA(SiMe3)3 as starting materials for further investigations.Thereby, we encountered highly interesting features of the molecular structure of NTPAH3 itself in the solid state, which distinguish this acid from related aminoalkyl functionalized phosphinic and phosphonic (and carboxylic) acids.Both the preference of formation of O−H⋅⋅⋅O hydrogen bonds over the protonation of the intramolecular base (i.e., the alkylamine N atom) as well as the capability of solvent-dependent formation of intramolecular vs. intermolecular (O=P−O−H)3 H-bond trimers render crystalline NTPAH3 an interesting hydrogen bonding system.While the former stabilizes monomeric NTPAH3, the latter renders this acid an interesting candidate as a building block for hydrogen-bonded organic frameworks (HOFs) [17][18][19].As hydrogen bonding itself is of current interest (e.g., with respect to spectroscopic properties [20] and as a bond type that may complement other bond types in H-bond cross-linked materials [21]), we decided to have a closer look at this particular H-bond system of NTPAH3.
Synthesis and characterization of NTPA(SiMe 3 ) 3 were carried out under an atmosphere of dry argon utilizing standard Schlenk techniques.Solution NMR spectra ( 1 H, 13 C, 29 Si, 31 P) (cf.Figures S1-S7 in the supporting information) were recorded on a Nanobay Crystals 2024, 14, 662 3 of 18 400 MHz spectrometer (Bruker Biospin, Ettlingen, Germany). 1 H, 13 C and 29 Si chemical shifts are reported relative to Me 4 Si (0 ppm), either as internal reference or in accordance with the shift of the solvent signal ((CD 3 ) 2 SO at δ 39.5 ppm in case of the 13 C NMR spectrum of NTPAH 3 ), 31 P chemical shifts are reported relative to 85% H 3 PO 4 (from an external calibration) set at 0 ppm.Solid-state NMR experiments (for spectra cf.Figures S8-S13 in the supporting information) were performed on an Avance HD 400 MHz WB spectrometer (Bruker Biospin, Ettlingen, Germany) with ZrO 2 rotors.The 13 C and 31 P spectra were recorded using a 4 mm triple resonance CP MAS DVT probe with a spinning rate of 10 kHz.The 1 H spectra were measured on a 2.5 mm CP MAS VTN probe with a spinning rate of 30 kHz.The 31 P NMR chemical shift was referenced to 85% H 3 PO 4 using NH 4 H 2 PO 4 as external secondary standard.The 13 C chemical shift was referenced to TMS using adamantane as external secondary standard.Cross-polarization NMR experiments were carried out with 1 ms contact time for 31 P and 2 ms for 13 C.An 80% ramp was used for 31 P and a 70% ramp for 13 C.The recycle delay of all 13 C and 31 P CP experiments was 30 s and for 1 H 10 s.IR spectra were measured at room temperature using a Nicolet 380 instrument (Thermo Fisher, Waltham, MA, USA).The solid material was ground with dry KBr in a mortar and pressed into a pellet.For each measurement, 32 scans were collected using wavenumbers from 400 cm −1 to 4000 cm −1 .The spectra were corrected for background (prior to each measurement the background was collected using a freshly prepared KBr pellet).
For single-crystal X-ray diffraction analyses, crystals were selected under an inert oil and mounted on a glass capillary (which was coated with silicone grease).Diffraction data were collected on a Stoe IPDS-2/2T diffractometer (STOE, Darmstadt, Germany) using Mo Kα-radiation.Data integration was performed with the STOE software XArea version 2.3.The structures were solved using SHELXT and refined with the full-matrix least-squares methods of F 2 against all reflections with SHELXL-2019/3 [22][23][24].All non-hydrogen atoms were anisotropically refined, C-bound hydrogen atoms were isotropically refined in idealized position (riding model), and hydrogen atoms of OH groups were located as residual electron density peaks and were refined without restraints.For details of data collection and refinement, see Appendix A, Table A1.Graphics of molecular structures were generated with ORTEP-3 [25,26] and POV-Ray 3.7 [27].CCDC 2365392 (NTPAH 3 P ), 2365391 (NTPAH 3 M ) and 2365393 (NTPA(SiMe 3 ) 3 ) contain the supplementary crystal data for this article.These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures/ (accessed on 25 June 2024).
The geometry optimizations of isolated molecules were carried out with ORCA 5.0.3 [28] using the restricted PBE0 functional with a relativistically recontracted Karlsruhe basis set ZORA-def2-TZVPP [29,30] for all atoms, scalar relativistic ZORA Hamiltonian [31,32], atom-pairwise dispersion correction and with the Becke-Johnson damping scheme (D3BJ) [33,34].Calculations were started from the molecular structures obtained by single-crystal X-ray diffraction analysis.Numerical frequency calculations were performed to prove convergence at the local minimum after geometry optimization and to obtain the Gibbs free energy (293.15K).The crystal structures of NTPAH 3 P , and NTPAH 3 M were optimized with TURBOMOLE rev.V7-7-1 [35] using the restricted PBE functional with a basis set pob-TZVP and RI-J auxiliary basis set for all atoms.A grid size of m3 and atom-pairwise dispersion correction with a Becke-Johnson damping scheme (D3BJ) [33,34] were used.During the periodic boundary optimization, the redundant coordinates were optimized and cell parameters were held constant.At the final geometry, a single-point calculation using PBE0 functional was performed.QTAIM analyses were performed with Multiwfn 3.8 [36] starting from the results obtained with the PBE0 functional.Graphics were generated using Chemcraft version 1.8 (Build 164) [37] or TURBOMOLE rev.V7-7-1 [35].The R-factor for the match of 3-fold symmetry of the individual optimized molecular structures was evaluated with Chemcraft [37].
A coarse crystalline product (used for single-crystal X-ray diffraction analyses) was obtained according to a related protocol but using more hexamethyldisilazane as solvent, i.e., 2.08 g (4.34 mmol) of NTPAH 3 P in 20 mL (ca.15.4 g, 95.6 mmol) of hexamethyldisilazane.The greater amount of solvent caused a lower yield of isolated crystalline product (2.24 g, 3.22 mmol, 74%).
Compound NTPAH 3 M (C 21 H 24 NO 6 P 3 ).In a 10 mL Schlenk flask, NTPA(SiMe 3 ) 3 (0.569 g, 0.818 mmol) was dissolved in chloroform (5 mL) and anhydrous EtOH (1 mL) was added carefully (chloroform phase layered with ethanol), whereupon a small amount of white precipitate formed upon contact between the two phases within the first minute.Eventually, long crystalline needles of the product formed upon standing overnight.Thereafter, the solvent was decanted, and the white solid was dried in vacuo.Yield: 0.361 g (0.753 mmol, 92%).M.p.The nitrilotriphosphinic acid NTPAH 3 in our study was prepared according to a previously published protocol [38] (Scheme 1), and the product obtained in this procedure (referred to as modification NTPAH 3 P ; the superscript index P indicates its H-bonded polymeric nature in the solid state) was used for our study.Silylation of NTPAH 3 in excess hexamethyldisilazane (which served both as the silylating reagent and as the solvent) afforded the tris(trimethylsilyl) derivative NTPA(SiMe 3 ) 3 , which crystallized from the reaction solution upon cooling to room temperature.This compound is highly soluble in chloroform and, in this solution, highly sensitive toward protolysis (e.g., alcoholysis).Thus, deliberate alcoholysis of NTPA(SiMe 3 ) 3 in chloroform afforded long needles of NTPAH 3 in a new modification (referred to as modification NTPAH 3 M , the superscript index M indicates its monomeric nature caused by exclusively intramolecular H-bonds).

Syntheses of NTPAH3 and Its Trimethylsilyl Ester NTPA(SiMe3)3
The nitrilotriphosphinic acid NTPAH3 in our study was prepared according to a previously published protocol [38] (Scheme 1), and the product obtained in this procedure (referred to as modification NTPAH3 P ; the superscript index P indicates its H-bonded polymeric nature in the solid state) was used for our study.Silylation of NTPAH3 in excess hexamethyldisilazane (which served both as the silylating reagent and as the solvent) afforded the tris(trimethylsilyl) derivative NTPA(SiMe3)3, which crystallized from the reaction solution upon cooling to room temperature.This compound is highly soluble in chloroform and, in this solution, highly sensitive toward protolysis (e.g., alcoholysis).Thus, deliberate alcoholysis of NTPA(SiMe3)3 in chloroform afforded long needles of NTPAH3 in a new modification (referred to as modification NTPAH3 M , the superscript index M indicates its monomeric nature caused by exclusively intramolecular H-bonds).

Crystallographic Analysis of the Molecular Structures of NTPA(SiMe3)3, NTPAH3 P and NTPAH3 M
Compound NTPA(SiMe3)3 crystallized in the trigonal space group type R3 with two independent thirds of molecules in the asymmetric unit (Figure 2, Appendix A Table A1).Their N atoms are located on crystallographic 3-fold rotation axes (Figure 2b,d).The Si−O bond lengths (1.6756( 14) and 1.6760( 14) Å) are similar to those encountered with trimethylsilyl phosphate O=P(OSiMe3)3 (1.674(3) Å, [39]) and a derivative of a cyclic phosphinic acid, (Me3SiO [40]).The latter was the only hit in a CSD search [41] for crystallographically characterized triorganosilyl derivatives of phosphinic acids.Thus, the crystal structure of NTPA(SiMe3)3 bears some novelty in this regard.Further metric data of these molecules (Table 1) will be discussed in the context of the further analysis of the acid NTPAH3.Compound NTPA(SiMe 3 ) 3 crystallized in the trigonal space group type R3 with two independent thirds of molecules in the asymmetric unit (Figure 2, Appendix A Table A1).Their N atoms are located on crystallographic 3-fold rotation axes (Figure 2b,d).The Si-O bond lengths (1.6756( 14) and 1.6760(14) Å) are similar to those encountered with trimethylsilyl phosphate O=P(OSiMe 3 ) 3 (1.674(3)Å, [39]) and a derivative of a cyclic phosphinic acid, (Me 3 SiO)(O=)P[-C(SiMe 3 ) 2 -CH 2 -CH=C(SiMe 3 )-] (1.672(2) Å, [40]).The latter was the only hit in a CSD search [41] for crystallographically characterized triorganosilyl derivatives of phosphinic acids.Thus, the crystal structure of NTPA(SiMe 3 ) 3 bears some novelty in this regard.Further metric data of these molecules (Table 1) will be discussed in the context of the further analysis of the acid NTPAH 3 .
Crystals of both modifications NTPAH 3 P and NTPAH 3 M were analyzed by singlecrystal X-ray diffraction (Figures 3 and 4, Tables 1 and A1).Both modifications are trigonal (space group types P3c1 and R3c, respectively), and their asymmetric units consist of one third of a molecule of NTPAH 3 with its nitrogen atom located on a crystallographically imposed 3-fold rotation axis.Even though the three P-atoms within one molecule exhibit the same chirality, both crystal structures accommodate the respective (R,R,R)/(S,S,S)pair of enantiomers because of the c glide in their space groups types.In both cases, the N atom is not protonated; i.e., the phosphinic acid moieties are retained.Hence, the molecules are not zwitterionic.This was an unexpected observation, as in both cases the trialkylamine N atoms' lone pairs are essentially vacant (they are not involved in any other hydrogen bonds, the structures do not contain any other H-bond donors such as ammonium ions, water molecules etc., which could interfere with the N-located lone pair).This can be attributed to the involvement of all of the P(O)(OH) groups' hydrogen atoms in cyclic hydrogen bond patterns, i.e., R 3  3 (12) motifs [42] of the type (O=P-O-H) 3 (vide infra).The difference between the molecular conformations of NTPAH 3 contained in its two modifications is essentially based on an approximate 110 • torsion about the CH 2 -P bond (N-C-P-C torsion angles are 66.7(2) • in NTPAH 3 P and 176.3(1) • in NTPAH 3 M ), as shown in Figure 3.This conformational difference gives rise to entirely different inter-and intramolecular interactions.While in modification NTPAH 3 P , the three phenyl groups form a calix shape and the P(O)(OH) moieties point away from the central N atom (Figure 4a,c), in modification NTPAH 3 M , the phenyl groups represent the periphery, and the three P(O)(OH) moieties are oriented toward the central 3-fold rotation axis (Figure 4b,d).In the latter case, this orientation results in the formation of a cyclic hydrogen bond system (indicated by the thin blue lines in Figure 4d).In modification NTPAH 3 P , a related R 3 3 (12) hydrogen bond motif is formed, also about a crystallographically imposed 3-fold rotation axis, but in an intermolecular manner (cf. Figure 4e).The molecular conformation of NTPAH 3 in NTPAH 3 P resembles the conformation of NTPA(SiMe 3 ) 3 .
Crystals 2024, 14, x FOR PEER REVIEW 6 of 19    third of a molecule of NTPAH3 with its nitrogen atom located on a crystallographically imposed 3-fold rotation axis.Even though the three P-atoms within one molecule exhibit the same chirality, both crystal structures accommodate the respective (R,R,R)/(S,S,S)-pair of enantiomers because of the c glide in their space groups types.In both cases, the N atom is not protonated; i.e., the phosphinic acid moieties are retained.Hence, the molecules are not zwitterionic.This was an unexpected observation, as in both cases the trialkylamine N atoms' lone pairs are essentially vacant (they are not involved in any other hydrogen bonds, the structures do not contain any other H-bond donors such as ammonium ions, water molecules etc., which could interfere with the N-located lone pair).This can be attributed to the involvement of all of the P(O)(OH) groups' hydrogen atoms in cyclic hydrogen bond patterns, i.e., R  4b,d).In the latter case, this orientation results in the formation of a cyclic hydrogen bond system (indicated by the thin blue lines in Figure 4d).In modification NTPAH3 P , a related R (12) hydrogen bond motif is formed, also about a crystallographically imposed 3-fold rotation axis, but in an intermolecular manner (cf. Figure 4e).The molecular conformation of NTPAH3 in NTPAH3 P resembles the conformation of NTPA(SiMe3)3.For a comparison of the individual molecules, a set of selected corresponding bond lengths and angles of compounds NTPA(SiMe 3 ) 3 , NTPAH 3 P and NTPAH 3 M is listed in Table 1.The N-C-P angles in NTPA(SiMe 3 ) 3 and NTPAH 3 P are noticeably wider than the tetrahedral angle, and we interpret this widening as originating from the steric congestion about the CH 2 groups.This angle is much closer to the tetrahedral angle in the cage structure of NTPAH 3 M , which lacks that kind of steric repulsion of the N-and P-bound substituents.In the compounds studied here, the coordination spheres about the P atoms are distorted tetrahedrally, which is to be expected from the VSEPR effect of the P=O bond.For a comparison of the individual molecules, a set of selected corresponding bond lengths and angles of compounds NTPA(SiMe3)3, NTPAH3 P and NTPAH3 M is listed in Table 1.The N-C-P angles in NTPA(SiMe3)3 and NTPAH3 P are noticeably wider than the tetrahedral angle, and we interpret this widening as originating from the steric congestion about the CH2 groups.This angle is much closer to the tetrahedral angle in the cage structure of NTPAH3 M , which lacks that kind of steric repulsion of the N-and P-bound M , the corresponding angles are significantly wider (116.0(1)• ).We attribute this angle widening to the strain associated with the cage formation   S16).Whereas these parts of the fingerprint plots are similar for the two modifications, great differences are evident for the long-range interactions part of the maps, where C-C, C-H and H-H interactions can be found, and C-C interactions are responsible for the greatest difference.Figure 6 shows that the long-range C-C interactions in NTPAH 3 P are caused by the calix shape created by the three phenyl groups about the 3-fold rotation axis.The faces of the phenyl rings inside the calix are thus protected from closer packing.In contrast, in NTPAH 3 M , the phenyl groups are more accessible for intermolecular packing from all sides.In addition to the closer C-C interactions, a larger fraction of C-C contacts on the packing of NTPAH ).It is well known that there are problems associated with locating H atoms from X-ray diffraction data.In order to rule out the possibility that this deviation of different refined O-H bond lengths has greater influence on our Hirshfeld surface analysis, we performed the same analysis with structure models that were obtained by a refinement with idealized OH groups (riding model, H atom attached with the ShelX-code AFIX 147).In principle, it reflects the same findings (same appearance of fingerprint maps, same d norm ranges).A representation of the contributions of contacts (corresponding to Figure 7, including the models with idealized OH groups) is included in the Supplementary Material, Figure S17.fraction data.In order to rule out the possibility that this deviation of different refined O−H bond lengths has greater influence on our Hirshfeld surface analysis, we performed the same analysis with structure models that were obtained by a refinement with idealized OH groups (riding model, H atom attached with the ShelX-code AFIX 147).In principle, it reflects the same findings (same appearance of fingerprint maps, same dnorm ranges).A representation of the contributions of contacts (corresponding to Figure 7, including the models with idealized OH groups) is included in the supplementary material, Figure S17.

Computational Analyses of NTPAH3 P and NTPAH3 M
For energetic comparison of the two modifications of NTPAH3 and for closer inspection of the H-bond situation and its influence on bond lengths, we have optimized the molecular structures of NTPAH3 P and NTPAH3 M both as isolated molecules (NTPAH3 P OPT-1 and NTPAH3 M OPT-1) and in their periodic crystal environment (NTPAH3 P OPT-CRYST and NTPAH3 M OPT-CRYST).For details of the computational analyses, please see Section 2.1.and the supplementary material (Figures S18-S21, Tables S2-S5).

Computational Analyses of NTPAH3 P and NTPAH3 M
For energetic comparison of the two modifications of NTPAH3 and for closer inspection of the H-bond situation and its influence on bond lengths, we have optimized the molecular structures of NTPAH3 P and NTPAH3 M both as isolated molecules (NTPAH3 P OPT-1 and NTPAH3 M OPT-1) and in their periodic crystal environment (NTPAH3 P OPT-CRYST and NTPAH3 M OPT-CRYST).For details of the computational analyses,   S2-S5).
For both approaches of optimization of the molecular structures, the atomic coordinates obtained from crystallographic analyses were used as starting point, and optimizations were performed without constraints of symmetry operations.With respect to the latter, in all cases the 3-fold molecular symmetry was essentially retained in the local minima molecular conformations (with R-factors for the 3-fold symmetry match of 0. OPT-1 .These contributions serve as some compensation to the expected energy difference.Therefore, we analyzed the wave function features of the H-bonds to evaluate their energetic properties.Using quantum theory of atoms in molecules (QTAIM) analyses, we observed bond-critical points at the O-H•••O hydrogen bonds.Emamian et al. [46] reported that via the electron density at the bond critical point, the hydrogen bond strength can be estimated.For  The IR spectra of NTPAH 3 P and NTPAH 3 M (Figure 8) are characteristic fingerprints, which clearly distinguish between the two modifications.The most prominent difference is associated with the OH groups of these compounds.As reported earlier [47], the vibrational modes of phosphinic acids´OH groups in cyclic hydrogen bond situations may give rise to an "A-B-C"-pattern of broad bands of high intensity.These bands are located around 2560, 2200 and 1680 cm −1 for NTPAH 3 P and around 2630, 2190 and 1540 cm −1 for NTPAH 3 M .Notably, the "C" band is shifted to lower wavenumbers and gains in relative intensity over "A" and "B" bands for NTPAH 3 M .In the literature [47] it is interpreted as a sign of the increasing strength of the set of hydrogen bonds involved.Furthermore, a splitting of the "B" band is particularly obvious for NTPAH 3 P , and in the literature that splitting has been mentioned in the context of weaker H-bonds. 1 H MAS NMR spectroscopy of these solids also supports the presence of stronger H-bonds in NTPAH 3 M .As shown in Figure 9, the signal of the OH protons (at δ iso 13.6 ppm for NTPAH 3 P and at δ iso 16.6 ppm for NTPAH 3 M ) is sufficiently well resolved from the shift range of the aryl protons (the broad signal in the range 4-10 ppm) and thus clearly shows that the OH signal of NTPAH 3 M is shifted by ∆δ ca.+3 ppm.It is well known that 1 H NMR signals of protons in H-bond situations are shifted to higher frequencies and that this shift is more pronounced for nuclei in stronger H-bonds [48,49].This has been underlined by correlations of decreasing OH groups' 1 H NMR shielding with shortening in O•••O distances in series of carboxylic acids and phosphonic acids [48].Moreover, this shift difference of the OH signal represents the greatest difference in the 1 H MAS NMR spectra of these two compounds.NTPAH3 .Notably, the "C" band is shifted to lower wavenumbers and gains in relative intensity over "A" and "B" bands for NTPAH3 M .In the literature [47] it is interpreted as a sign of the increasing strength of the set of hydrogen bonds involved.Furthermore, a splitting of the "B" band is particularly obvious for NTPAH3 P , and in the literature that splitting has been mentioned in the context of weaker H-bonds. 1 H MAS NMR spectroscopy of these solids also supports the presence of stronger Hbonds in NTPAH3 M .As shown in Figure 9, the signal of the OH protons (at δiso 13.6 ppm for NTPAH3 P and at δiso 16.6 ppm for NTPAH3 M ) is sufficiently well resolved from the shift range of the aryl protons (the broad signal in the range 4−10 ppm) and thus clearly shows that the OH signal of NTPAH3 M is shifted by Δδ ca.+3 ppm.It is well known that 1 H NMR signals of protons in H-bond situations are shifted to higher frequencies and that this shift is more pronounced for nuclei in stronger H-bonds [48,49].This has been underlined by correlations of decreasing OH groups´ 1 H NMR shielding with shortening in O⋅⋅⋅O distances in series of carboxylic acids and phosphonic acids [48].Moreover, this shift difference of the OH signal represents the greatest difference in the 1 H MAS NMR spectra of these two compounds.The 13 C MAS NMR (Figure 10) and 31 P MAS NMR spectra (Figure 11) reveal further spectroscopic differences between NTPAH3 P and NTPAH3 M .In the former, the notable shift difference Δδ of ca. 10 ppm between the signals of the CH2 carbon atoms (at δiso 54 ppm for NTPAH3 P and at δiso 64 ppm for NTPAH3 M ) indicates the involvement of these groups in different bonding situations in the two modifications (i.e., as part of a cage motif in NTPAH3 M vs. absence of this motif in NTPAH3 P ).In contrast, the shift differences of the aromatic 13 C signals (in the range 125−135 ppm) are less pronounced.The 31 P MAS NMR signals (at δiso 34.2 ppm for NTPAH3 P and at δiso 37.7 ppm for NTPAH3 M ) also allow us to assign the modification to the respective solid.Both fingerprint features of the two modi- The 13 C MAS NMR (Figure 10) and 31 P MAS NMR spectra (Figure 11) reveal further spectroscopic differences between NTPAH 3 P and NTPAH 3 M .In the former, the notable shift difference ∆δ of ca. 10 ppm between the signals of the CH 2 carbon atoms (at δ iso 54 ppm for NTPAH 3 P and at δ iso 64 ppm for NTPAH 3 M ) indicates the involvement of these groups in different bonding situations in the two modifications (i.e., as part of a cage motif in NTPAH 3 M vs. absence of this motif in NTPAH 3 P ).In contrast, the shift differences of the aromatic 13

Conclusions
In general, nitrilotris(methylenephenylphosphinic) acid (NTPAH3) can be silylated using hexamethyldisilazane to afford the tris(trimethylsilyl) derivative, NTPA(SiMe3)3.The latter is sensitive toward protolysis, and alcoholysis in chloroform liberates the acid NTPAH3.The different solvents used for synthesis of NTPAH3 (aqueous hydrochloric acid vs. chloroform) give rise to the crystallization of two different modifications of this acid,

Conclusions
In general, nitrilotris(methylenephenylphosphinic) acid (NTPAH3) can be silylated using hexamethyldisilazane to afford the tris(trimethylsilyl) derivative, NTPA(SiMe3)3.The latter is sensitive toward protolysis, and alcoholysis in chloroform liberates the acid NTPAH3.The different solvents used for synthesis of NTPAH3 (aqueous hydrochloric acid vs. chloroform) give rise to the crystallization of two different modifications of this acid, i.e., NTPAH3 P and NTPAH3 M , respectively.As both modifications exhibit similar stability (shown by computational analysis), the formation of these modifications can be attributed

Conclusions
In general, nitrilotris(methylenephenylphosphinic) acid (NTPAH 3 ) can be silylated using hexamethyldisilazane to afford the tris(trimethylsilyl) derivative, NTPA(SiMe 3 ) 3 .The latter is sensitive toward protolysis, and alcoholysis in chloroform liberates the acid NTPAH 3 .The different solvents used for synthesis of NTPAH 3 (aqueous hydrochloric acid vs. chloroform) give rise to the crystallization of two different modifications of this

Figure 1 .
Figure 1.Selected multi-functional α-amino acids of the carboxylic, phosphinic and phosphonic acid types (I-VI) and the nitrilotris(methylenephenylphosphinic) acid (NTPAH3) studied herein.The current study will reveal the location of the acidic protons in the latter compound.

Figure 1 .
Figure 1.Selected multi-functional α-amino acids of the carboxylic, phosphinic and phosphonic acid types (I-VI) and the nitrilotris(methylenephenylphosphinic) acid (NTPAH 3 ) studied herein.The current study will reveal the location of the acidic protons in the latter compound.
12) motifs[42] of the type (O=P−O−H)3 (vide infra).The difference between the molecular conformations of NTPAH3 contained in its two modifications is essentially based on an approximate 110° torsion about the CH2−P bond (N−C−P−C torsion angles are 66.7(2)° in NTPAH3 P and 176.3(1)° in NTPAH3 M ), as shown in Figure3.This conformational difference gives rise to entirely different inter-and intramolecular interactions.While in modification NTPAH3 P , the three phenyl groups form a calix shape and the P(O)(OH) moieties point away from the central N atom (Figure4a,c), in modification NTPAH3 M , the phenyl groups represent the periphery, and the three P(O)(OH) moieties are oriented toward the central 3-fold rotation axis (Figure

Figure 3 .
Figure 3. Thermal ellipsoid plots (50% probability) of the asymmetric units of NTPAH3 in its modifications NTPAH3 P (a) and NTPAH3 M (b), view along the P−CH2 bond.
Thus, the widest angles are associated with X-P=O (X = C, O) moieties.Interestingly, the O-P=O angles are slightly wider than the C-P=O angles, and two reasons can be considered for this phenomenon: The C(Ph)-P=O angle is particularly small (smaller than the C(CH 2 )-P=O angle) because of C-H•••O=P attraction, which involves the P=O moiety and an ortho-H atom of the phenyl group.The C(CH 2 )-P=O angle is still smaller than the O-P=O angle.The P-O bond may feature partial multi-bond character (in case of the P-O-Si moiety because of the electropositive silyl substituent, which renders the P-O-bound oxygen electron-rich, and in the case of the P-O-H moiety, because of the hydrogen bridge, which renders the P-O-bound oxygen electron-rich and also lowers the P=O double bond character).That would explain the enhanced O-P=O repulsion vs. relatively lowered C-P=O repulsion.

Figure 4 .
Figure 4. Molecular structures of NTPAH3 in its modifications NTPAH3 P (in sections (a,c,e,f)) and NTPAH3 M (in (b,d)) with thermal displacement ellipsoids at the 50% probability level (for clarity, C-bound hydrogen atoms are not depicted).Sections (a,b) show a selected view of each molecule with the atoms of the asymmetric unit labelled, (c,d) show the molecules viewed along the crystallographic c axis.Their nitrogen atoms (N1) are located on crystallographic 3-fold rotation axes, in both cases the whole molecules are generated by the symmetry operations (−y+1, x−y+1, z) and (−x+y, −x+1, z).For NTPAH3 M these symmetry operations create a trimeric intramolecular hydrogen bond system (shown in (d), labels with * and ** indicate symmetry equivalents).In NTPAH3 P intermolecular hydrogen bonds in a polymeric network (shown in (f)) give rise to a related (O=P−O−H)3 motif (magnified section of interest from (f) shown in (e), these symmetry equivalents * and ** are generated by symmetry operations −y+1, x−y, z and −x+y+1, −x+1, z, respectively).

Figure 4 . 3 M
Figure 4. Molecular structures of NTPAH 3 in its modifications NTPAH 3 P (in sections (a,c,e,f)) and NTPAH 3 M (in (b,d)) with thermal displacement ellipsoids at the 50% probability level (for clarity, C-bound hydrogen atoms are not depicted).Sections (a,b) show a selected view of each molecule with the atoms of the asymmetric unit labelled, (c,d) show the molecules viewed along the crystallographic c axis.Their nitrogen atoms (N1) are located on crystallographic 3-fold rotation axes, in both cases the whole molecules are generated by the symmetry operations (-y+1, x-y+1, z) and (−x+y, −x+1, z).For NTPAH 3 M these symmetry operations create a trimeric intramolecular hydrogen bond system (shown in (d), labels with * and ** indicate symmetry equivalents).In NTPAH 3 P intermolecular hydrogen bonds in a polymeric network (shown in (f)) give rise to a related (O=P-O-H) 3 motif (magnified section of interest from (f) shown in (e), these symmetry equivalents * and ** are generated by symmetry operations -y+1, x-y, z and −x+y+1, −x+1, z, respectively).The inter-vs.intramolecular O-H•••O hydrogen bonding in NTPAH 3 P and NTPAH 3 M , respectively, results in further differences between the two crystal structures: In NTPAH 3 P the C-N-C angles are 109.6(2)• .Thus, they are similar to the C-N-C angles in NTPA(SiMe 3 ) 3 (110.4(1)and 111.1(1) • ).In NTPA 3M , the corresponding angles are significantly wider (116.0(1)• ).We attribute this angle widening to the strain associated with the cage formation

3 PNTPAH 3 M
Figure 5 shows the fingerprint plots (d e vs. d i ) of these analyses.Note: Because of the analysis of the asymmetric unit, the N-C bonds (and adjacent intramolecular N-H interactions) are also shown in the fingerprint plots, even though they are intramolecular features and determine the lowest d norm values in both analyses.The O-H interactions are dominated by the O-H•••O hydrogen bonds.Therefore, these contributions are representative of the (intermolecular and intramolecular, respectively) O-H•••O hydrogen bond motifs in NTPAH and , respectively.(C-H•••O contacts are also present in both modifications; they contribute to the longer distance O-H interactions.For comparison of fingerprint plots (d e vs. d i ) of all O-H interactions see Figure

Figure 5 .
Figure 5. Fingerprint plots (de vs. di) of the Hirshfeld surface analyses (performed with CrystalExplorer version 21.5, revision 608bb32 [43]) of (a) the asymmetric unit of the crystal structure of NTPAH3 P and (b) the asymmetric unit of the crystal structure of NTPAH3 M .Note: The N−C interactions correspond to the N−C bonds, which connect the asymmetric unit with the two further symmetry equivalent parts of the molecule.

Figure 5 . 19 Figure 6 .
Figure 5. Fingerprint plots (d e vs. d i ) of the Hirshfeld surface analyses (performed with Crys-talExplorer version 21.5, revision 608bb32 [43]) of (a) the asymmetric unit of the crystal structure of NTPAH 3 P and (b) the asymmetric unit of the crystal structure of NTPAH 3 M .Note: The N-C interactions correspond to the N-C bonds, which connect the asymmetric unit with the two further symmetry equivalent parts of the molecule.Crystals 2024, 14, x FOR PEER REVIEW 11 of 19

Figure 7 .
Figure 7. Percentage distribution (with respect to the area on the Hirshfeld surface) of the contacts of the asymmetric units of the crystal structures of NTPAH3 P and NTPAH3 M .Note: The N−C and N−H interactions (shown in the black box) correspond to the N−C bonds and interactions of N with their CH2 H atoms. Thus, they are intramolecular interactions in both cases.

Figure 6 . 19 Figure 6 .
Figure 6.Selected section of the Hirshfeld surface analysis (performed with CrystalExplorer version 21.5, revision 608bb32 [43]) of the asymmetric unit of the crystal structure of NTPAH 3 P showing (a) the area of C-C interactions on the isosurface (d norm ) and (b) the corresponding section of the fingerprint plot (d e vs. d i ).

Figure 7 .
Figure 7. Percentage distribution (with respect to the area on the Hirshfeld surface) of the contacts of the asymmetric units of the crystal structures of NTPAH3 P and NTPAH3 M .Note: The N−C and N−H interactions (shown in the black box) correspond to the N−C bonds and interactions of N with their CH2 H atoms. Thus, they are intramolecular interactions in both cases.

Figure 7 .
Figure 7. Percentage distribution (with respect to the area on the Hirshfeld surface) of the contacts of the asymmetric units of the crystal structures of NTPAH 3 P and NTPAH 3 M .Note: The N-C and N-H interactions (shown in the black box) correspond to the N-C bonds and interactions of N with their CH 2 H atoms. Thus, they are intramolecular interactions in both cases.

3. 3 . 3 M 3 P OPT- 1 and NTPAH 3 MOPT- 1 ) 3 POPT-CRYST and NTPAH 3 M
Computational Analyses of NTPAH 3 P and NTPAHFor energetic comparison of the two modifications of NTPAH 3 and for closer inspection of the H-bond situation and its influence on bond lengths, we have optimized the molecular structures of NTPAH 3 P and NTPAH 3 M both as isolated molecules (NTPAH and in their periodic crystal environment (NTPAH OPT-CRYST ).For details of the computational analyses, please see Section 2.1.and the Supplementary Material (Figures S18-S21, Tables

3 MOPT- 1 3 POPT- 1 3 MOPT-1 and NTPAH 3 POPT- 1 3 P OPT- 1 also
), with an R-factor of 0.000 representing a perfect C 3 symmetry).Comparison of the total energies revealed that the two modifications exhibit very similar stability with NTPAH 3 M OPT-CRYST being only marginally less stable than NTPAH 3 P OPT-CRYST by 0.34 kcal•mol −1 (PBE) or 1.66 kcal•mol −1 (single-point calculation with PBE0).As an isolated molecule, NTPAH is noticeably more stable than NTPAH by −20.6 kcal•mol −1 (PBE0).This difference is mainly attributed to the presence vs. absence of the O-H•••O hydrogen bonds in NTPAH , respectively.Nonetheless, the energy involved in formation of the R 3 3 (12) H-bond trimer can be expected to exceed that value.Dimerization energies of phosphinic acids (formation of R 2 2 (8) motifs by two O-H•••O hydrogen bonds) were experimentally determined at 21 ± 6 to 60 ± 10 kcal•mol −1[44,45], which would imply H-bond energies around 10.5 to 30 kcal•mol −1 per H-bond and thus energies around 31.5 to 90 kcal•mol −1 for related Hbond cyclo-trimers.However, the energy of the molecular conformation of NTPAH gains contributions from intramolecular interactions, which are associated with the formation of the (P-Ph) 3 calix and which are absent in NTPAH 3 M

NTPAH 3 MOPT- 1 , 3 MOPT-CRYST and NTPAH 3 P 3 M 3 M 3 M OPT- 1 ( 3 M OPT- 1 Crystals 3 M 3 POPT-CRYST and NTPAH 3 M
an average H-bond energy of 17 kcal•mol −1 per H-bond is observed, and for each of the sets, NTPAH OPT-CRYST , it is ca.20 kcal•mol −1 .These values are in the above-mentioned expected range of 10.5 to 30 kcal•mol −1 per Hbond.The energetic difference between the H-bonds of 0.4 kcal•mol −1 (20.3 kcal•mol −1 for NTPAH OPT-CRYST and 19.9 kcal•mol −1 for NTPAH 3 P OPT-CRYST ) vaguely indicates stronger H-bonds in NTPAH 3 M but is too marginal for a reliable conclusion.Closer inspection of the bonds involved in the H-bond systems in NTPAH 3 P and NTPAH 3 M (Table 2) indicates differences between the strength of the R 3 3 (12) H-bond trimers in these two modifications.While in the silyl derivative NTPA(SiMe 3 ) 3 the P-O bond is ca.0.10 Å longer than the P=O bond, this bond length difference is less pronounced in the crystal structures of the acids NTPAH 3 P and NTPAH 3 M (with differences of 0.05 and 0.02 Å, respectively).The enhanced averaging of P-O and P=O bond lengths in NTPAH could be an indication of a stronger H-bond system with respect to NTPAH 3 P , and the shorter O•••O distance (by 0.04 Å) in NTPAH 3 M provides further support.These observations may (at least in part) also originate from unresolved O-H•••O vs. O•••H-O disorder in the crystal structures, and therefore further support is essential to confirm this hypothesis.Comparison of NTPAH 3 P OPT-1 (single molecule devoid of H-bonds) and NTPAH single molecule with intramolecular H-bond system) already shows that P=O and P-O bonds are elongated and shortened, respectively, upon H-bond formation, and elongation of the O-H bond is observed as well.However, the additional interactions in the crystal packing cause further changes, which is evident from the comparison of NTPAH .Longer P=O and P-O bonds (with respect to the related bonds in the isolated molecule) are observed, and features of stronger H-bond systems are revealed.In NTPAH OPT-CRYST , a longer O-H bond, shorter H•••O distance and an overall shorter O•••O distance is observed.Comparison of the two optimized molecular structures in the crystal environment (NTPAH OPT-CRYST ) reveals that these modifications exhibit very similar H-bond features.Whereas in NTPAH 3M the slightly longer O-H bond may indicate a stronger H-bond system, the slightly longer O•••O distance is indicative of the opposite.Hence, the structural differences are less pronounced than expected from the crystallographic analysis.Therefore, further support will be delivered by solid-state 1 H NMR and IR spectroscopy (cf.Section 3.4).Last but not least, the different C-N-C bond angles in NTPAH 3P and NTPAH 3 M were also confirmed by the computational analyses.Hence, the wide C-N-C angles are a characteristic feature of the cage structure of the molecule in NTPAH 3 M .

Figure 9 .
Figure 9. 1 H MAS NMR spectra of (a) NTPAH3 P and (b) NTPAH3 M recorded at MAS frequencies of 30 kHz.(The probe background has not been subtracted.).

Figure 9 .
Figure 9. 1 H MAS NMR spectra of (a) NTPAH 3 P and (b) NTPAH 3 M recorded at MAS frequencies of 30 kHz.(The probe background has not been subtracted).

19 Figure 10 .
Figure 10. 13 C CP MAS NMR spectra of (a) NTPAH3 P and (b) NTPAH3 M recorded at MAS frequencies of 10 kHz.The asterisks (*) indicate spinning sidebands of the aryl-C signals.

Table 1 .
Selected corresponding bond lengths (Å) and angles (deg) in the crystal structures of 1 Two individual sets of parameters are given in accordance with the asymmetric unit.2Sum of angles about P=O (X = O, C).
To account for related kinds of interactions in a comparable manner, a Hirshfeld surface analysis was performed for the asymmetric units (which are one third molecule in each case), and therefore the O-H•••O hydrogen bonds were accounted for in the same manner (Selected d norm isosurface plots of the Hirshfeld surface analyses are contained in the Supplementary Material Figures S14 and S15).The d norm ranges (−1.092. ..+2.229 for NTPAH 3 P , −1.094. ..+1.167 for NTPAH 3 M ) vary noticeably, and the pronounced upper value of +2.229 in NTPAH 3 P indicates less efficient packing in this modification (well in accordance with the volume per molecule, which is much larger for NTPAH 3 P than for NTPAH 3 M with 596 vs. 549 Å 3 , respectively).
1The O-H bond lengths from XRD analyses are not taken into consideration for comparison because of the inherent problem of uncertainty of determination of H-atom positions by X-ray diffraction.2Formolecules or structures with multiple independent bonds or atom distances of the same kind, the average value is reported here.