P,P,P′,P′-Tetraisopropyl(1,4-phenylenebis(hydroxymethylene))bis(phosphonate)

Abstract

We report the synthesis and molecular structure as determined by single-crystal X-ray diffraction of P,P,P′,P′-tetraisopropyl(1,4-phenylenebis(hydroxymethylene))bis(phosphonate). The compound was fully characterized by ¹H, ¹³C, and ³¹P NMR spectroscopy, IR spectroscopy, and Mass Spectrometry.

1. Introduction

The chemistry of α-hydroxyphosphonates has been widely explored as they find uses in drug design [1,2] and in many other industries for their biological properties [3,4,5]. They are easily produced from the reaction of an aldehyde with a phosphonate under basic conditions [6,7,8] (Scheme 1).

In comparison, bis-α-hydroxyphosphonates (prepared using dialdehydes) are less prevalent in the literature; however, they have been reported to serve as useful precursors for phosphorus-containing polyurethanes, which have excellent flame-retardant properties [9,10]. Hydoxy-functionalised bisphosphonic acids have recently been employed in the preparation of fluorescent MOFs, the detection of nitroaromatic explosives, and drug-delivery systems for cancer-induced osteolytic metastasis [11,12,13]. Recently, Mou et al. reported the synthesis of a series of 1,4- and 1,3- bis-substituted phosphonates using dimethyl or diethyl phosphonate from the corresponding aromatic dialdehyde catalyzed by triethylamine [14] (Scheme 2).

These products were characterized by NMR (¹H, ¹³C, and ³¹P) and HRMS; however, the crystal structures of these materials were not elucidated. Herein, we report the synthesis of P,P,P′,P′-tetraisopropyl(1,4-phenylenebis(hydroxymethylene))bis(phosphonate) (1) using the same method as Mou [10].

2. Results and Discussion

2.1. Synthesis and Spectroscopy

Compound 1 was synthesized by the Pudovik reaction [15] adapted by Mou [10]. Diisopropyl phosphonate was reacted with terephthalaldehyde in a 2:1 molar ratio in the presence of catalytic triethylamine (Scheme 3). The product was isolated by aqueous work-up, and the crude material recrystallised from methanol to afford 1 as colourless crystals.

As 1 has two chiral carbon atoms, it can exist as two diastereoisomers (meso- and rac-); therefore some of the peaks in the ¹³C DEPTQ NMR spectrum (in dimethyl sulfoxide-d₆) appear slightly broadened or with ‘shoulders’ (Supporting Information Figure S4). In DMSO-d₆ the ³¹P{¹H} NMR spectrum shows a sharp singlet at δ_P 20.2 ppm, which is shifted slightly downfield from δ_P 4.5 ppm in diisopropyl phosphonate. This suggests both phosphonate groups are identical chemically and magnetically. The methyl groups in diisopropyl phosphonate are magnetically inequivalent, showing overlapping doublets at δ_H 1.38 and 1.37 ppm with a shared ³J_HH of 6.2 Hz with the CH group. However, in 1, the methyl groups appear as three distinct doublets between δ_H 1.21 and 1.08 ppm, again with a ³J_HH of 6.2 Hz with the CH group of the isopropyl. Significant NMR parameters are provided in

Table 1. Significant NMR parameters of 1 recorded in DMSO-d₆ in ambient conditions (¹H, 400 MHz, ¹³C 101 MHz, ³¹P, 162 MHz).

1H NMR				13C NMR		31P{1H} NMR
δP–CH (ppm)	2JHP, 3JHH (Hz)	δOH (ppm)	3JHP, 3JHH (Hz)	δP–C (ppm)	1JCP (Hz)	δP (ppm)
4.81	12.7, 6.0	6.07	15.6, 6.0	69.6	165.6	20.2

. The hydroxyl hydrogen atom appears as a doublet of doublets at δ_H 6.07 ppm with a ³J_HP coupling of 15.6 Hz, and a ³J_HH coupling of 6.0 Hz to the CH group at δ_H 4.81 ppm, which is also a doublet of doublets with a ²J_HP of 12.7 Hz. In the ¹³C DEPTQ NMR spectrum the P–CH–OH peak appears at δ_C 69.6 ppm with a ¹J_CP of 165.6 Hz. These NMR parameters are closely related to the ethoxy phosphonate previously reported [10].

2.2. Structural Study

Crystals of 1 that were of suitable quality for single-crystal X-ray diffraction were grown from vapour diffusion of petroleum ether into a solution of 1 in methanol. The structure of racemic 1 was confirmed from these crystals, which adopt the centrosymmetric space group P$\overline{1}$ (Figure 1).

The molecule is centrosymmetric around the centroid of the aromatic ring. The bonds are all of typical length with P1–O1 showing clear double-bond character at 1.474(1) Å, and the other P–O bonds at 1.568(1) Å [16]. The phosphorus adopts a distorted tetrahedral geometry with angles ranging from 102.98(7)° to 116.00(7)° (

Table 2. Selected bond lengths (Å), angles (°), torsion angles (°) and displacements (Å) for 1.

P1–O1	1.474(1)	C7–O7	1.414(2)
P1–O2	1.568(1)	P1–C7	1.824(1)
P1–O3	1.568(1)	O1···H7 a	1.72(3)
C7–P1–O1	112.35(7)	O1–P1–O3	113.64(7)
C7–P1–O2	102.98(7)	O2–P1–O3	103.99(6)
C7–P1–O3	106.82(7)	O7–H7···O1 a	176(2)
O1–P1–O2	116.00(7)	P1–O1···H7 a	138.5(9)
O7–C7···P1–O1	66.6(1)
Out-of-plane displacements b
P1	1.638	O7	−0.426

^a Symmetry element: 1-x, 1-y, 2-z. ^b measured from the mean C₆ plane of the xylene ring.

).

The structure has three points of disorder; two are rocking of the isopropyl groups around their C–O bonds, and the third is positional disorder of the hydroxyl group (O7) as an inversion of the chiral carbon (C7) (Supporting Information Figure S1). In both disordered positions, the hydroxyl group forms hydrogen bonds to P1–O1 of adjacent molecules, forming C(10) chains containing ${\mathrm{R}}_2^2$(10) dimers along [0 0 1] (H···O 1.72(3) Å and 1.65(2) Å, O–H···O 176(2) and 177(2)°, for H7 and H7A, respectively) (Figure 2).

The HRMS spectrum shows two major peaks. The molecular ion with sodium (M + Na⁺) is visible at 489.1771 amu (calcd. 489.1783), confirming that the identity of 1 matches the expected formula (Supporting Information Figure S9), and the ‘dimer’ with an incorporated sodium ion (2M+Na⁺) is visible at 955.3650 amu (calcd. 955.3668).

3. Materials and Methods

All synthetic manipulations were performed in air. Glassware was dried in an oven (ca. 110 °C) prior to use. Diisopropyl phosphonate was purchased from ThermoFisher (Birmingham, UK) and used as received. All other chemicals were used as provided from the laboratory inventory without further purification. The IR spectrum was recorded on a Perkin Elmer Spectrum Two instrument with a Deuterated Triglycine Sulfate (DTGS) detector and diamond Attenuated Total Reflectance (ATR) attachment (Bruker, Billerica, MA, USA). The High-Resolution Mass Spectrometry (HMRS) data were acquired from the University of St Andrews Mass Spectrometry Service. All NMR spectra were recorded using a Bruker Avance III 400 MHz spectrometer at 20 °C (Bruker, Billerica, MA, USA). The ¹³C spectrum was recorded using the DEPTQ-135 pulse sequence with broadband proton decoupling. Tetramethylsilane was used as external standard for ¹H and ¹³C NMR (δ_H/δ_C 0.00 ppm), and 85% aqueous H₃PO₄ was used as the external standard for ³¹P NMR (δ_P 0.00 ppm). Where possible, the residual solvent signal was used as a secondary reference (d₆-DMSO, δ_H 2.50, δ_C 39.52 ppm). Spectra were analyzed using the MestReNova software package (Santiago de Compostela, Spain) (version 14).

3.1. Synthesis and Characterization

Terephthalaldehyde (0.67 g, 5 mmol) and diisopropyl phosphonate (1.66 g, 10 mmol) were dissolved in tetrahydrofuran (10 mL). To this, triethylamine (0.36 g, 0.5 mL, 3.6 mmol) was added with stirring. Stirring was maintained for a further 12 h in ambient conditions. After this time, the volatiles were removed under reduced pressure to afford a pale-yellow oil. This was dissolved in diethyl ether (20 mL), washed with distilled water (2 × 5 mL) and dried over magnesium sulfate. The residue was recrystallised from methanol to afford 1 (0.82 g, 35%) (Mp. 195–197 °C).

¹H NMR (400.3 MHz, d₆-DMSO) δ_H 7.37 (4H, s, ArC-H), 6.07 (2H, dd, ³J_HP 15.6, ³J_HH 6.0 Hz, C(H)OH), 4.81 (2H, dd, ³J_HP 12.7, ³J_HH 6.0 Hz, C(H)OH), 4.56–4.37 (2H, m, CH(CH₃)₂), 1.19 (12H, d, ³J_HH 6.3 Hz, 4 × CH(CH₃)₂), 1.17 (6H, ³J_HH 6.2 Hz, 2 × CH(CH₃)₂), 1.07 (6H, ³J_HH, 6.2 Hz, 2 × CH(CH₃)₂). ¹³C DEPTQ NMR (101.7 MHz, d₆-DMSO) δ_C 137.7 (Ar-qC), 126.8 (Ar-CH), 70.3–70.0 (m~d ²J_CP 17.1 Hz, P-CH(CH₃)₂), 69.6 (m~d, ¹J_CP 165.6 Hz, C(H)OH), 23.9 (s, 2 × CH(CH₃)₂), 23.6 (s, 1 × CH(CH₃)₂), 23.5 (s, 1 × CH(CH₃)₂). ³¹P{¹H} NMR (162.0 MHz, d₆-DMSO) δ_P 20.2 (s). HRMS (ESI+) m/z (%) Calcd. for C₂₀H₃₆O₈P₂Na 489.1783, found 489.1771 [M+Na] (100); Calcd. for C₄₀H₇₂O₁₆P₄Na 955.3668, found 955.3650 [2M+Na] (52). IR: ν_max (ATR/cm⁻¹) 3226b (ν_OH), 2980w (ν_CH), 1378w, 1209m, 993vs (ν_P=O), 576s.

3.2. X-Ray Crystallography

X-ray diffraction data for 1 were collected at 173 K using a Rigaku FR-X Ultrahigh Brilliance Microfocus RA generator/confocal optics with XtaLAB P200 diffractometer [Mo Kα radiation (λ = 0.71073 Å)]. Data were collected (using a calculated strategy) and processed (including correction for Lorentz, polarization and absorption) using CrysAlisPro [17]. The structure was solved by dual-space methods (SHELXT) [18] and refined by full-matrix least-squares against F² (SHELXL-2019/3) [19]. Both isopropyl groups in the asymmetric unit showed rocking disorder and were each refined in two parts with restrained geometry. The hydroxyl oxygen (O7) showed positional disorder as an inversion of chirality at C7 and was refined in two parts with C−O bonds restrained to be the same distance. Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were refined using a riding model except for the hydrogen atom on the major component of the hydroxide (O7), which was located from the difference Fourier map and refined isotropically subject to a distance restraint. All calculations were performed using the Olex2 interface [20]. Selected crystallographic data: C₂₀H₃₆O₈P₂, M = 466.43, triclinic, a = 7.8428(3), b = 7.9556(3), c = 10.5700(4) Å, α = 98.678(3), β = 98.247(3), γ = 105.917(4) °, U = 614.99(4) ų, T = 173 K, space group P$\overline{1}$ (no. 2), Z = 1, 13327 reflections measured, 2908 unique (R_int = 0.0384), which were used in all calculations. The final R₁ [I > 2σ(I)] was 0.0394 and wR₂ (all data) was 0.1094.