Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate

Olive, Gilles; Jacques, Alain

doi:10.3390/M275

Open AccessShort Note

Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate

by

Gilles Olive

^1,* and

Alain Jacques

²

¹

Unité de physique et de chimie des hauts polymères, Université catholique de Louvain, Bâtiment Bolztmann, Place Croix du Sud, 1, B-1348 Louvain-la-Neuve, Belgium

²

Unité CSTR, Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur, 1, B-1348 Louvain-la-Neuve, Belgium

^*

Author to whom correspondence should be addressed.

Molecules 2001, 6(12), M275; https://doi.org/10.3390/M275

Submission received: 1 December 2001 / Accepted: 15 December 2001 / Published: 20 December 2001

(This article belongs to the Section Molbank Section of Molecules, 1997-2001)

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Keywords:

diphosphorylation; triethylphosphite; pyrrolidone; bisphosphonate

The synthesis of the title compound is already described [1, 2] and we report here the fully optimized procedure. In a double walls flask, under nitrogen, phosphorus oxychloride (20 ml; 0.22 mol) is added for 1 h 00 time to a mixture at -7.5 °C of 2-pyrrolidinone (9.3 g; 0.11 mol) and triethylphosphite (35.1 g; 0.21 mol; 1.9 eq.). The reaction mixture is stirred for 1 hour at room temperature and then poured over a mixture of ice (200 g) and ammonia 30 % (400 ml). The aqueous layer is extracted with methylene chloride (3x100 ml) and then the latter is removed to obtain a yellow oil. The oil is dissolved in 100 ml of methylene chloride. An aqueous solution of hydrochloric acid (10 ml of 32 % HCl solution, 190 ml of water) is added (check that pH 1) and the aqueous layer is washed with methylene chloride (3x100 ml). A solution of sodium hydroxide (20 g of NaOH in 200 ml of water) is added up to pH 10 and the aqueous layer is extracted with methylene chloride (4x100 ml). The organic layer is dried over sodium sulfate, filtered and the removal of the solvent affords 1 (20.9 g; 58 %) as a colourless oil.

Formula: C₁₂H₂₇NO₆P₂.

Molecular weight: 343.13 g.mol^-1.

M.p: -36 °C.

B. _p: 140 °C under 6.10^-2 mmHg.

R_f: 0.39 (Acetone) ; 0.43 (CH₂Cl₂ / EtOH 19:1).

UV (EtOH, 25 °C): lmax (e) 205 (1622), 221 (1737), 264 (212) nm (mol^-1.dm³.cm^-1).

pKa: 3.5 - Krebs at 20 °C: 3.59 - Krebs at 37 °C: 3.47. [3]

IR (Neat): 3481 (n_NH); 2982 (n_CH2 ring + n_CH3 As.); 2932 (n_CH2 ethoxy); 2909; 2869 (n_CH3 Sym.); 1670 (d_NH); 1595; 1478; 1457 (d_CH2 ring + ethoxy); 1392 or 1368 (d_CHsp3 Sym.); 1324; 1293; 1243 (P=O); 1164 (P-OEt); 1098 (n_C-N); 1044; 968; 794; 732; 645; 580; 536 cm^-1.

Raman: 2979 (nCH2 ring + nCH3 As.); 2934 (nCH2 ethoxy); 2874 (nCH3 Sym.); 2778; 2725; 1594 (dNH in plane); 1482; 1458 and 1449 (dCH2 ring + ethoxy); 1394 or 1369 (dCHsp3 Sym.); 1289; 1240 (P=O); 1190; 1162 (P-OEt); 1100 (nC-N); 1027; 918; 877; 812; 757; 653; 291; 271 cm-1.

¹H-NMR: d in ppm referring to TMS (multiplicity, J in Hz) ; a, b, c, d and e as assigned in scheme.

Solvent	Frequency (MHz)	a	b	c	d	e
CDCl₃	400	2.92 (t, 6.4)	1.74(quint., 6.4)	2.16 (m)	4.07 (m)	1.20 (t, 7.0)1.20 (t, 6.8)
C₆D₆	400	2.88 (t, 6.5)	1.69 (quint., 6.5, 7.2)	2.42 (tt, 7.2^a, 17.7^b)	4.17 (m)	1.10 (t, 7.1)1.11 (t, 7.1)
D₂O	500	2.98 (t, 6.4)	1.87(quint., 6.4)	2.28 (tt, 7.2^a, 18.7^b)	4.21 (m)	1.34 (t, 7.1)
DMSO55 °C = 328 K	500	2.92 (t, 6.9)	1.74(quint., 7.2)	2.14 (tt, 7.2^a, 17.9^b)	4.08 (m)	1.23 (t, 7.2)
Acetone-d ^c₆	500	3.10 (t, 6.5)	1.91(quint., 6.8)	2.33 (tt, 7.2^a, 17.7^b)	4.26 (m)	1.38 (t, 7.1)
CDCl₃d	500	0.87 s	0.79 s	0.58 s	1.78 s	1.85 s

^a JH-H b JP-H

^c Additional: 3.28 (ls, NH)

^d Value of T1

¹³C-NMR: d in ppm referring to TMS (multiplicity, J_CP in Hz) (multiplicity, ¹JCH in Hz for CDCl₃ and Acetone-d6) ; (1), (2), (3), (4), (5) and (6) as assigned in scheme.

Solvent	Frequency (MHz)	(1)	(2)	(3)	(4)	(5)	(6)
CDCl₃	125	47.4 (t, 4.7)(t, 139.4)^a	26.1 (t, 3.7)(t, 133.8)^a	30.5 (t, 3.6)(t, 135.4)^a	61.7 (t, 152.3)	62.8 (t, 3.8)(tsext.^c, 148.3)^a63.3 (t, 3.6)(tsext.^c, 149.3)^a	^b (qh, 127.1)^ab(qh, 127.1)^a
C₆D₆	100	47.7 (t, 4.0)	26.5 (t, 3.1)	31.2 (t, 3.0)	62.8 (t, 151.8)	62.7 (t, 5.8)63.4 (t, 5.8)	16.5 (t, 7.2)16.6 (t, 5.5)
D₂O	125	47.0 (m)	25.4 (t, 3.1)	30.0 (m)	62.0	64.7(q, 3.8)	15.6 (t, 2.7)
DMSO_{30 °C = 303 K}	125	47.0	25.6	30.5	61.4 (t, 151.3)	62.3 (t, 3.6)62.6^b	16.3
DMSO_{55 °C = 328 K}	125	46.7 (t, 4.7)	25.3 (t, 3.7)	30.3 (t, 3.5)	61.6 (t, 151.7)	62.0 (t, 3.8)62.3 (t, 3.4)	15.9 (t, 3.1)16.0 (t, 2.3)
DMSO_{70 °C = 343 K}	125	46.9	25.6	30.6	62.1 (t, 151.5)	62.3 (t, 3.7)62.5 (t, 3.5)	16.2
Acetone-d₆	125	48.0 (t, 4.5)(t, 138.9)^a	26.7 (t, 3.6)(t, 133.2)^a	31.5 (d, 3.7)(t, 133.8)^a	62.9 (t, 151.8)	63.2 (t, 3.7)(t, 148.04)^a 63.6(d, 3.4)(t, 147.9)^a	16.8 (t, 3.8)(q, 130.5)^a

^a Proton coupled (multiplicity, ¹J_CH in Hz)

^b Unresolved triplet

^c Triplet of sextuplet

Variable temperature in DMSO at 63 MHz [4]

Temp.°C	Temp. K	(1)	(2)	(3)	(4)	(5)	(6)
30	303	46.9 (t, 4.7)	25.6 (t, 3.5)	30.5 (t, 3.2)	61.4 (t, 151.7)	62.3 (t, 3.8)62.6 (t, 3.6)	16.3 (t, 3.0)
50	323	46.9 (t, 4.8)	25.6 (t, 3.5)	30.5 (t, 3.2)	61.6a	62.3 (t, 3.8)62.5 (t, 3.6)	16.2 (t, 2.9)
60	333	46.9 (t, 4.7)	25.6 (t, 3.6)	30.5 (t, 3.2)	61.8 (t, 151.0)	62.3 (t, 3.8)62.5 (t, 3.6)	16.2 (t, 2.7)
70	343	46.9 (t, 4.8)	25.6 (t, 3.7)	30.5 (t, 3.2)	61.9^a	62.3 (t, 3.8)62.5 (t, 3.5)	16.2
90	363	46.9 (t, 4.8)	25.5 (t, 3.7)	30.5 (t, 3.2)		62.3 (t, 3.8)62.5 (t, 3.7)	16.1 (t, 2.5)
110	383	46.9 (t, 4.8)	25.5 (t, 3.7)	30.6 (t, 3.1)		62.3 (t, 3.9)62.5 (t, 3.7)	16.1

^a Only the central line

³¹P-NMR: d in ppm referring to external 85 % H₃PO₄

d (CDCl3, 40 MHz): 22.5 ppm.

d (CDCl₃, 162 MHz): 24.7 ppm.

d (C₆D₆, 40 MHz): 22.8 ppm.

da (Krebs at 20 °C, 162 MHz): 16.51 ppm - db (Krebs at 20 °C, 162 MHz): 24.09 ppm. [3]

da (Krebs at 37 °C, 162 MHz): 16.53 ppm - db (Krebs at 37 °C, 162 MHz): 24.18 ppm. [3]

T₁ (CDCl₃, 202 MHz): 1.89 s.

³¹P MAS NMR: d (10 KHz spinning at 200 K): 22.39 ppm. [5]

¹⁵N-NMR: d in ppm referring to external CD₃NO₂: d (CDCl₃, 50 MHz): -341.6 (t, J_NP = 8.6) ppm.

d (C₆D₆, 50 MHz): -340.7 (t, J_NP = 8.7) ppm.

¹⁷O-NMR: d in ppm referring to external H₂O: d (DMSO, 68 MHz): 95.4 (P=O) ppm.

d (Acetone d₆, 68 MHz): 84.6 (P=O) and 53.9 (P-O) ppm.

Supplementary Material

References and Notes

Olive, G.; Le Moigne, F.; Mercier, A.; Rockenbauer, A.; Tordo, P. J. Org. Chem. 1998, 63, 9095–9099. [CrossRef]
Olive, G.; van Genderen, M. H. P. Magn. Reson. Chem. 2000, 38(5), 379–381. [CrossRef]
Pietri, S.; Miolan, M .; Martel, S.; Le Moigne, F.; Blaive, B.; Culcasi, M. J. Biol. Chem. 2000, 275(26), 19505–19512. [CrossRef] [PubMed]
Olive, G.; Jacques, A. To be published.
Millot, Y.; Olive, G.; Magusin, P. To be published.

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Olive, G.; Jacques, A. Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate. Molecules 2001, 6, M275. https://doi.org/10.3390/M275

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Olive G, Jacques A. Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate. Molecules. 2001; 6(12):M275. https://doi.org/10.3390/M275

Chicago/Turabian Style

Olive, Gilles, and Alain Jacques. 2001. "Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate" Molecules 6, no. 12: M275. https://doi.org/10.3390/M275

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