Synthesis of new benzylic di-, tri-, and tetraphosphonic acids as potential chelating agents

Article abstract of DOI:10.1080/10426507.2010.502161

Chemical Equation Presented New di-, tri-, and tetraphosphonic acids were synthesized starting from four o-hydroxymethyl phenol derivatives and obtained in three steps in good overall yield. The phosphonic acids were isolated and purified using semi-preparative C18 HPLC column. The new compounds were characterized using different spectroscopic methods (1H, 13C, and 31P NMR; ESI MS; and MSn, IR). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.502161

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of New Benzylic Di-, Tri-,
and Tetraphosphonic Acids as Potential
Chelating Agents
Nabila Aliouane a , Jean-Jacques Hélesbeux b , Tahar Douadi a ,
Mustayeen A. Khan b , Gilles Bouet b , Salah Chafaa a & Olivier Duval
b
a Université Ferhat Abbas, Sétif, Faculté des Sciences de l’Ingénieur,
Laboratoire d’Électrochimie des Matériaux Moléculaires et des
Complexes , Sétif, Algérie
b Université d’Angers, UFR Sciences Pharmaceutiques et Ingénierie
de la Santé, IFR QUASAV 149, Laboratoire Substances d’Origine
Naturelle et Analogues Structuraux , Angers, France
Published online: 19 Feb 2011.
To cite this article: Nabila Aliouane , Jean-Jacques Hélesbeux , Tahar Douadi , Mustayeen A.
Khan , Gilles Bouet , Salah Chafaa & Olivier Duval (2011) Synthesis of New Benzylic Di-, Tri-, and
Tetraphosphonic Acids as Potential Chelating Agents, Phosphorus, Sulfur, and Silicon and the Related
Elements, 186:2, 354-364, DOI: 10.1080/10426507.2010.502161
To link to this article: http://dx.doi.org/10.1080/10426507.2010.502161
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Phosphorus, Sulfur, and Silicon, 186:354–364, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.502161
SYNTHESIS OF NEW BENZYLIC DI-, TRI-,
AND TETRAPHOSPHONIC ACIDS AS POTENTIAL
CHELATING AGENTS
Nabila Aliouane,1 Jean-Jacques He´lesbeux,2 Tahar Douadi,1
Mustayeen A. Khan,2 Gilles Bouet,2 Salah Chafaa,1
and Olivier Duval2
1Universite´ Ferhat Abbas, Se´tif, Faculte´ des Sciences de l’Inge´nieur, Laboratoire
´
d’Electrochimie des Mate´riaux Mole´culaires et des Complexes, Se´tif, Alge´rie
2Universite´ d’Angers, UFR Sciences Pharmaceutiques et Inge´nierie de la Sante´,
IFR QUASAV 149, Laboratoire Substances d’Origine Naturelle et Analogues
Structuraux, Angers, France
GRAPHICAL ABSTRACT
Abstract New di-, tri-, and tetraphosphonic acids were synthesized starting from four o-
hydroxymethyl phenol derivatives and obtained in three steps in good overall yield. The phos-
phonic acids were isolated and purified using semi-preparative C18 HPLC column. The new
compounds were characterized using different spectroscopic methods (1H, 13C, and 31P NMR;
ESI MS; and MSn, IR).
Keywords Characterization; polyphosphonic acids; synthesis
INTRODUCTION
Phosphonates belong to a class of molecules containing one or more R-PO(ORꢁ)2
groups. Phosphonate additives are used worldwide in a broad spectrum of applications,
including household and industrial detergents,1–3 industrial water treatment,4,5 industrial
Received 23 March 2010; accepted 14 June 2010.
Address correspondence to Olivier Duval, Universite´ d’Angers, UFR Sciences Pharmaceutiques et Inge´nierie
de la Sante´, Laboratoire Substances d’Origine Naturelle et Analogues Structuraux, SONAS EA 921, IFR QUASAV
149, 16 Boulevard Daviers, F-49045, Angers Cedex 01, France. E-mail: olivier.duval@univ-angers.fr
354

NEW BENZYLIC DI-, TRI-, AND TETRAPHOSPHONIC ACIDS
355
cleaners, and enhanced oil recovery operations, as well as in corrosion control.6–8 Recently
the effect of phosphonates used in Russian heat-power engineering on the corrosion of
carbon steel in deaerated delivery water at 90◦C has been studied. It was shown that intro-
duction of phosphonates reduced the susceptibility of steel to local corrosion.9 This class
of products also finds applications in medicinal chemistry as antiviral agents, in such a
way that they can be considered as analogues of natural pyrophosphates.10–12 The search
for new, more efficient, more specific polyphosphonate chelating agents represents a con-
siderable challenge and is of great interest in the field of environmental remediation. In
the design of inorganic hybrid metal complexes, the phosphonic acids are of potential
interest because of their high number of hydrogen bond acceptors and their remarkable
acidity (higher than those of the corresponding carboxylic acids). Therefore these ligands
have been successfully used as extractants,13 and their complexing properties have been
examined.14. Bo¨hmer et al. have synthesized a series of mono- and bisphosphonic acids
stemming from phenols.15 Organo-phosphonic acids have been used as complexing agents
due to their strong binding ability and the stability of the complexed species.15–22 Recently
calix[4]resorcinolarenes with phosphinoylalkyl substituents with acidic phosphonate frag-
ments were shown to be efficient extracting agents of the metal ions of the lanthanum group
from acidic solutions.23,24 Structurally related derivatives, calix[4]arene methylenebispho-
sphonic acids, also displayed strong inhibition of calf intestine alkaline phosphatase.25
Another recent report showed that derivatives of calix[4]arenes bearing phosphonic acids
or lithium methyl phosphonate groups behave as host molecules, as they form complexes
with ephedrine, norephedrine, and noradrenaline hydrochlorides in phosphate buffer at
deuterated phosphate buffer pD 7.3.26 In order to enhance the number of complexing sites,
we have used as starting material the methylene-4,4ꢁ-bis(phenol) backbone 1. At the same
time, this allowed us to keep some kind of flexibility, as the two aromatic rings were linked
via a methylene group. In this article, we describe the synthesis of new compounds bearing
two, three, and four phosphonic acid functions.
RESULTS AND DISCUSSION
Synthesis of the Phosphonic Acids 7–10
To access the intermediate phosphonic esters, various approaches are possible
starting from the phenol derivatives. Baimukhametov et al. reported the preparation
of diethyl 5-allyl-2-hydroxybenzyl phosphonate in 33% yield via the intermediate 2-
diethylaminomethyl-4-allyl phenol, derived from the corresponding substituted phenol
derivative.27 We could also either use o-hydroxybenzyl alcohols or convert them first into
the corresponding halogen derivatives prior to the reaction with a trialkyl phosphite. This
latter option may require either stirring with 48% HBr in acetic acid28,29 or two additional
steps, which could limit the final overall yield: activation of the hydroxyl group, followed
by its displacement (with a sodium halide, for example). On the other hand, halomethy-
lation of substituted phenols has also been reported recently, but the yields decrease with
increasing the steric demand of the substituents.30
o-Hydroxybenzyl alcohols have already been reported to react with trialkyl phos-
phites. Ivanov and Ageeva initiated those reactions leading, after rearrangement, according
to the authors, to cyclic phosphites.31 The proposed mechanism was first called into ques-
tion by Miles et al.32 and was later confirmed by means of NMR analysis by Chasar.33 The

356
N. ALIOUANE ET AL.
latter author could show that phosphonates were formed when o-hydroxybenzyl phenols
reacted with trialkyl phosphites in DMF.
Considering all these previous studies and results, we decided to develop what we
considered to be the most straightforward pathway to synthesize our target phosphonic
acids: (i) phenol-formaldehyde reaction with alkaline catalyst; (ii) Michaelis–Arbuzov
reaction involving the corresponding alcohols and trialkyl phosphite for several hours
following the modifications reported by Vogt and colleagues15,34; and (iii) hydrolysis of the
ester products.
It has to be mentioned that 4,4ꢁ-methylene bis[2,6-bis(hydroxymethyl)phenol] 5 was
already obtained from phenol in the presence of an excess of formaldehyde under various
basic conditions, albeit with a very low yield.35–38 The influence of the basic catalyst on the
phenol-formaldehyde reaction mechanism and kinetics has been previously investigated
by Grenier-Loustalot et al.39 When bis(4-hydroxyphenyl)methane 1 was used as starting
material, substitution occurred in the ortho and orthoꢁ positions leading to 5 with 20%
yield.40 Keeping in mind the results reported by Perrin et al.,37 we slightly modified the
experimental conditions, using LiOH as a base rather than NaOH in the presence of 1 as
starting material.
A mixture of the diphenol 1, an aqueous solution of lithium hydroxide, and formalde-
hyde (ratio, 1:1:4) was stirred for 24 h at room temperature to afford a mixture of tetrahy-
droxymethyl derivative 5, trihydroxymethyl derivative 4, dihydroxymethyl derivatives (3a
+ 3b), and monohydroxymethyl derivative 2 (Scheme 1). These compounds were purified
and isolated by silica gel flash column chromatography with yields of 25%, 25%, 14%,
and 4%, respectively. Using a controlled excess amount of formaldehyde of 2 and 10 molar
equivalents led to the mixture (3a + 3b) with 75% yield and to compound 5 with 70%
yield, respectively. The mixture (3a + 3b) was used as such for the following steps. It
must be noted that the monohydroxymethyl compound 2 was not considered for further
investigations.
The direct reaction of the o-hydroxybenzyl alcohol with trialkylphosphite has been
previously developed to prepare phenolic benzylphosphonate esters, with the phenolic
group in o-position relative to the phosphonomethyl group.34 As already reported and
demonstrated by Vogt, the ortho-phenol function is essential to make this modification of
the Arbusov procedure efficient. Thus the tetrahydroxymethyl derivative 5 was mixed with
a slight excess of trimethyl phosphite, and the resulting mixture was heated progressively
1
up to 80◦C and left for 4 h at this temperature. A H NMR analysis of the crude mixture
confirmed the formation of the expected phosphonate ester 6. Unfortunately, purification
by silica gel chromatography led to the pure product with only 3% yield. To overcome
this problem encountered during the purification process, we decided to perform directly
the hydrolysis step on the crude ester 6. Among the different procedures known to make
such a transformation, we used the very mild conditions previously developed by Bo¨hmer
et al.15 Applying this strategy with pure ester 6 showed to be successful leading to a
quantitative yield. As has already been reported for the reaction of ortho-hydroxybenzyl
alcohols with trialkyl phosphites, the phenolic function appeared also in this case to be
essential for a successful hydrolysis of the methyl phosphonate groups to the corresponding
acid.15 Assistance by neighboring functional groups has been previously invoked for the
hydrolysis mechanism of salicyl phosphates.41,42 As a hypothesis, a similar participation of
the ortho-phenol function could be involved in the synthesis of phosphonic acids from the
corresponding esters.

NEW BENZYLIC DI-, TRI-, AND TETRAPHOSPHONIC ACIDS
357
HO
a)
+
HO
OH
HO
OH
2
(4%)
1
HO
HO
HO
HO
OH
OH
+
+
OH
HO
3a
3b
(3a + 3b: 14%)
HO
HO
HO
OH
OH
HO
HO
HO
OH
OH
OH
+
4
5
(25%)
(25%)
a) (CH2O)n, LiOH, H2O, RT, 24h
Scheme 1
The unpurified ester 6 was then heated in a water/methanol solution at 90◦C in a sealed
tube for 30 h (Scheme 2). The classical procedure, consisting of heating with HCl, led to
slightly lower yields, although reaction times were sometimes shorter. HPLC purification,
using a semi-preparative C18 column with an acidic elution system (0.1% aqueous solution
of formic acid/acetonitrile, 90:10), allowed the isolation of the pure tetraphosphonic acid 7
with 76% yield over two steps. This result confirmed that the previous yield of 3% for 6 was
really linked to a problem occurring during the purification step. We can imagine that an
unexpected hydrolysis occurred, and the corresponding acids could not be eluted from the
silica gel column. Therefore, intermediate esters had to be used unpurified as the starting
material of the hydrolysis reaction in order to optimize the yield of the final phosphonic
acids.
This two-step procedure was then applied to compound 4 leading to the triphospho-
nic acid 8 with 64% yield (Scheme 3). The diacids 9 and 10, prepared using the same
experimental conditions starting from the mixture of alcohols 3a and 3b, were separated
using the HPLC purification procedure described above and obtained with 65% and 25%
yield, respectively.
Negative ion electrospray ionization (ESI), with double octopoles and ion trap in-
struments, was chosen to record the mass spectroscopy data for the acids 7–10.43,44 Mass
spectra of these derivatives showed peaks corresponding to double and/or triple charged
ions, losses of water from these ions, and formation of sodium adducts from double charged
ions. The [M-H]− ions for the different compounds were observed at m/z = 574.9 and 480.8
for 7 and 8, respectively, and at m/z = 386.8 for both isomers 9 and 10.

358
N. ALIOUANE ET AL.
O
O
P
HO
HO
HO
OH
OH
OH
H3CO
P
OCH3
CH3O
HO
CH3O
OCH3
OH
OCH3
a)
H3CO
P
P
OCH3
5
6
O
O
O
O
P
HO
HO
P
OH
OH
OH
HO
OH
OH
OH
OH
b)
P
P
7
O
O
a) P(OCH3)3, 80°C; b) CH3OH/H2O, 90°C, sealed tube
Scheme 2
[M-2H]2− ions were observed for compounds 7, 8, and 10 at m/z = 286.9, 239.7, and
192.7, respectively. It must be noted that the peak corresponding to a double deprotonation
was not observed for isomer 9. This may point out that for the other acids, double depro-
tonation occurred for two functions located on separated aromatic rings; for compound 9
both acid functions are on the same ring and the second deprotonation is not favored.
In the case of compound 7, the fragmentation pattern of the ion at m/z = 286.9
provided by ion trap MSn experiments could be explained by the loss of one, two, three,
and four water molecules producing ions at m/z = 277.92, 268.9, 259.89, and 250.85,
respectively. The first two losses of H2O could be the result of a dehydration of a phosphonic
acid moiety to yield a −PO2 group, as proposed by Huikko et al.44 The third and fourth loss
of H2O can follow two distinct pathways: dehydration between an OH group of a phosphonic
O
O
P
O
HO
HO
P
OH
HO
HO
P
OH
HO
OH
OH
OH
OH
HO
OH
OH
P
P
O
O
8
9
O
O
HO
P
P
OH
OH
HO
OH
OH
10
Scheme 3

NEW BENZYLIC DI-, TRI-, AND TETRAPHOSPHONIC ACIDS
359
moiety and the spatially close acidic phenol proton giving rise to an oxaphosphole structure,
or delocalization of the negative charge of a singly deprotonated phosphonic acid and
capture of the phenolic proton, leading to a phenolate appendage and a new −PO2 group.
Nevertheless, formation of a five-membered ring has already been invoked during
the degradation of alkyl polyphosphonates, though via the dehydration of two phosphonic
acid moieties. In both cases, there was just one phosphonic acid function left on each
benzene ring, while the third and fourth losses occurred. Participation of another type of
acidic proton—the phenolic ones—could be involved in the rearrangement of these ions.
Eventually this hypothetical process could give rise to oxaphosphole rings, which were
proved to be stable when synthesized by flash vacuum pyrolysis of arylphosphites.45–48
Moreover, in the case of compound 7, [M-2H+Na]− and [M-3H+2Na]− ions were
observed at m/z = 596.9 and 618.9, respectively. [M-3H]3− ion at m/z = 190.8 was observed
only for compound 7, proving that, for particular cases, deprotonation could occur on two
phosphonic acid moieties located on the same benzene ring. The fragmentation of this ion
with the successive loss of one, two, and three water molecules leads to the ions at m/z =
184.9, 178.9, and 172.8, respectively.
These different dehydration pathways were confirmed by MSn experiments with the
intensity of the parent ions decreasing and/or vanishing and at the same time the intensity
of peaks corresponding to losses of water increasing. The dehydration pathways proposed
for compound 7 are shown in Scheme 4.
CONCLUSION
We have describe here a straightforward and efficient three-step synthesis leading to
novel bisphenyl structures bearing methylene phosphonic acid groups and two phenolic
functions with satisfactory overall yields. Using the optimized conditions (i) working with
10 equivalents of formaldehyde, (ii) reaction with triethylphosphite, (iii) hydrolysis of the
crude ester, and (iv) HPLC purification, allowed the synthesis of the highly substituted
phosphonic acid 7 with 53% yield. Characterization and MSn degradation studies of the
different ions have been performed for the new phosphonic acids. The study of the chelating
properties of these new polyfunctionalized structures, especially with divalent and trivalent
cations, is currently ongoing and will be reported and discussed soon.
EXPERIMENTAL
Melting points were determined with a Bu¨chi 510 apparatus. IR spectra were recorded
as potassium bromide pellets with a Bruker FT IR Vector 22 spectrophotometer. TLC
was performed on a DC Alufolien Kieselgel 60 F254 (VWR). Column chromatography
was performed using silica-gel 60 (0.040–0.063 mm, SDS). NMR spectra were recorded
with a Jeol GX instrument operating at 270 MHz (1H), 67.5 MHz (13C), and 109.38
MHz (31P). Chemical shifts (δ-scale) are given in parts per million values downfield from
tetramethylsilane (Me4Si) (1H, 13C) or phosphoric acid (85% H3PO4) (31P). Low resolution
mass spectra were recorded with a Jeol JMS 700 B/E instrument in the ESI negative mode
(ESI−, ion source temperature: 200◦C, electron energy: 80 eV, accelerating voltage: 8 keV)
or with a Bruker Daltonics Esquire 3000 Plus (ESI−) instrument equipped with double
octopoles and an ion trap. Samples were dissolved in a 50/50 mixture of CH3CN/H2O.
The alcohol derivatives were isolated and purified by silica gel column chromatog-
raphy using a gradient ethyl acetate/dichloromethane as eluting solvent. Purification of

360
N. ALIOUANE ET AL.
O
O
P
HO
HO
P
OH
OH
OH
HO
OH
OH
OH
OH
P
P
O
O
-H+
-2H+
-3H+
O
O
O
P
O
O
O
P
-O
P
OH
-O
P
P
O-
-O
P
O-
O-
OH
HO
OH
OH
OH
OH
OH
HO
OH
OH
OH
OH
OH
HO
OH
OH
OH
OH
HO
P
P
OH
HO
P
P
OH
HO
P
P
m/z 574.9
-H2O
m/z 286.9
-H2O
m/z 190.8
-H2O
O
O
O
O
O
O
O
O
P
O
O
P
O
O
-O
P
OH
-O
P
O-
-O
P
P
O-
O-
OH
HO
OH
OH
OH
OH
HO
OH
OH
OH
OH
HO
OH
OH
OH
O
O
O
HO
P
P
HO
P
P
P
P
m/z 556.7
-H2O
m/z 277.9
-H2O
m/z 184.8
-H2O
O
O
O
O
O
O
O
O
O
O
O
O
P
-O
P
P
OH
-O
P
P
O-
-O
P
O-
O-
OH
HO
OH
OH
OH
HO
OH
OH
OH
HO
O
OH
O
O
O
O
O
P
P
P
P
P
P
m/z 538.7
-H2O
m/z 268.9
-H2O
m/z 178.8
-H2O
O
O
O
O
O
O
O
O
P
O
O
P
O
P
O
P
-O
P
-O
P
O-
-O
O-
O-
O
OH
OH
HO
OH
HO
O
O
O
OH
O
O
O
O
O
P
P
P
P
P
P
m/z 520.7
-H2O
m/z 259.9
-H2O
m/z 172.8
O
O
O
O
O
O
O
P
O
P
O
P
O
P
-O
-O
O-
O
O
OH
O
O
O
O
O
O
m/z 502.7
m/z 250.8
P
P
P
P
O
O
O
O
Scheme 4
the phosphonate derivatives was performed with a Hewlett-Packard 1100 HPLC system
using semi-preparative C18 column (250 × 25 mm) with a mixture of aqueous formic acid
solution pH = 3/acetonitrile (90/10) at a flow rate of 4 mL/min. Peaks were detected by
ultraviolet absorption with a diode array detector.

NEW BENZYLIC DI-, TRI-, AND TETRAPHOSPHONIC ACIDS
361
Synthesis of the Alcohols 2, 3a, 3b, 4, and 5: General Procedure
In a modification of the already described procedure,24 1 mol of bis(4-
hydroxyphenyl)methane 1 (2 g), 1 mol of LiOH (0.24 g) dissolved in water (2.3
mL) and 4 mol of 37% aqueous formaldehyde solution (3 mL) were mixed at room tem-
perature and stirred for 24 h. The mixture was then neutralized with H2SO4 (1N), extracted
with ethyl acetate (10 mL), and dried over sodium sulfate. The crude product was separated
by column chromatography (elution with a gradient of ethyl acetate/dichloromethane from
40% to 100% of ethyl acetate).
4,4ꢀ-Methylenebis[2,6-bis(hydroxymethyl)phenol] (5). Yield = 25% (20%
[20]); mp = 155◦C; IR (KBr), ν(cm−1): 3482s (OH), 3030w (arom. C-H), 1612m (arom.
C C), 1253s (arom. C-OH), 1070s (CH2-OH), 762m (CH2). 1H NMR (270 MHz, CD3OD):
δ = 3.78 (s, 2H, Ph-CH2-Ph), 4.65 (s, 8H, CH2-OH), 6.98 (s, 4H, arom-H). 13C NMR
(67.5 MHz, CD3OD): δ = 41.5 (Ph-CH2-Ph), 62.1 (CH2-OH), 128.1 (C-CH2-OH), 128.5
(CH), 134.1 (C-CH2-C), 152.8 (C-OH). MS (ESI): [M-H]− m/z obs. 319.1197 (m/z exp.
319.1181).
4-[4-Hydroxy-3-(hydroxymethyl)benzyl]-2,6-bis(hydroxymethyl)phenol
(4). Yield = 25%; mp = 136◦C; IR (KBr), ν(cm−1): 3416s (OH), 3030w (arom. C-H),
1613m (arom. C C), 1265s (arom. C-OH), 1072s (CH2-OH), 760m (CH2). 1H NMR (270
MHz, CD3OD): δ = 3.77 (s, 2H, Ph-CH2-Ph), 4.58 (s, 2H, CH2OH), 4.65 (s, 4H, CH2OH),
6.65 (d, J = 8.0 Hz, 1H, arom-H); 6.89 (dd, J = 8.0 Hz, 2.0 Hz, 1H, arom-H), 6.96 (s, 2H,
arom-H), 7.06 (d, J = 2.0 Hz, 1H, arom-H). 13C NMR (67.5 MHz, CD3OD): δ = 41.5
(Ph-CH2-Ph), 61.2 (CH2-OH), 62.2 (CH2-OH), 115.8 (CH), 128.1 (C-CH2-OH), 128.3
(C-CH2-OH), 128.5 (CH), 129.5 (CH), 129.6 (CH), 134.0 (C-CH2-C), 134.3 (C-CH2-C),
152.8 (C-OH), 154.3 (C-OH). MS (ESI-): [M-H]− m/z obs. 289.0434 (m/z exp. 289.1076).
4-(4-Hydroxybenzyl)-2,6-bis(hydroxymethyl)phenol (3a) and 4,4ꢀ-
methylenebis[2-(hydroxy-methyl)phenol] (3b). A mixture of 3a and 3b (yield =
14%) was obtained from the chromatographic separation. The mass spectrum indicated
only one value for this isomeric mixture (MS-ESI [M-H]− m/z obs. 259.0028, m/z exp.
1
259.0970). The H NMR analysis showed a 1:3 ratio in favor of the asymmetric isomer
3a, whose 1H NMR spectrum exhibits two singlets corresponding to non coupled protons,
versus 3b, which displays an ABX spin system located in the aromatic region. The
mixture was used without further purification. 13C NMR (67.5 MHz, CD3OD): δ = 41.3
(Ph-CH2-Ph), 41.4 (Ph-CH2-Ph), 61.2 (CH2-OH), 62.1 (CH2-OH), 115.8 (CH), 116.0
(CH), 128.1 (C-CH2-OH), 128.3 (C-CH2-OH), 128.5 (CH), 129.6 (CH), 129.7 (CH),
130.7 (CH), 134.1 (C-CH2-C), 134.3 (C-CH2-C), 152.8 (C-OH), 154.3 (C-OH), 156.4
(C-OH). MS (ESI-): [M-H]− m/z obs. 259.0028 (m/z exp. 259.0970).
Synthesis of the Phosphonic Acids: General Procedure
According to the conditions for the Michaelis–Arbuzov reaction, each fraction (0.1
mol) was introduced into a two-necked, 100 mL, round-bottom flask equipped with a reflux
condenser. 0.105 mol of P(OMe)3 was added for every CH2OH group in one portion, and
the mixture was heated to 80◦C for 4 h. The excess of trimethylphosphite was co-evaporated
under reduced pressure with diethyl ether. The alkyl ester was then hydrolyzed by heating
in a mixture of MeOH/H2O. Following this procedure, compounds 7–10 were obtained.
Octomethyl {methylenebist(2-hydroxy-5,1,3-phenylene)bismethylene]}
tetraphosphonate (6). After evaporation of the excess of trimethyl phosphite, the

362
N. ALIOUANE ET AL.
residue was purified by silica gel column chromatography with MeOH/ethyl acetate (20/80):
yield = 3%. 1H NMR (270 MHz, CDCl3): δ = 3.16 (d, J = 21.4 Hz, 8H, CH2-P), 3.62 (d,
J = 10.7 Hz, 24 H, PO-CH3), 3.72 (s, 2H, Ph-CH2-Ph), 6.87 (s, 4H, arom-H). 13C NMR
(67.5 MHz, CDCl3): δ = 27.7 (d, JPC = 137.0 Hz, CH2-P), 39.9 (s, Ph-CH2-Ph), 53.1 (t,
JPC = 3.0 Hz, OCH3), 120.2 (t, JPC = 6.5 Hz, C-CH2-P), 130.7 (t, JPC = 5.0 Hz, CH),
133.8 (t, JPC = 2.5 Hz, C-CH2-C), 151.6 (t, JPC = 5.5 Hz, C-OH). MS-ESI: [M-H]− m/z
obs. 687.0150 (m/z exp. 687.1295).
{Methylenebis[(2-hydroxy-5,1,3-phenylene)bismethylene]}tetraphos-
phonic acid (7). Keeping in mind the poor yield obtained after purification for the
ester 6, this latter was directly hydrolyzed. For the hydrolysis, the ester 6 (0.2 mmol) was
dissolved in MeOH (5 mL) and water (20 mL). The solution was heated in a sealed tube
at 90◦C for 30 h. The solvent was then removed in vacuo. The residue was eventually
purified by HPLC (C18 column) with a 90/10 aqueous formic acid solution at pH =
3/acetonitrile mixture as eluent at a flow rate of 4 mL/min. The product peak detected at
280 nm appeared at retention times of 50–70 min. The pure fractions were collected and
concentrated under reduced pressure to give compound 7 as a brown solid with 76% yield.
1
IR (KBr), ν(cm−1): 1652w, broad (POH), 1218s (P O), 1106s, 930s, 994s (P-OH). H
NMR (270 MHz, D2O): δ = 3.04 (d, JPH = 20.7 Hz, 8H, CH2-P), 3.68 (s, 2H, Ph-CH2-Ph),
6.93 (s, 4H, arom-H). 13C NMR (67.5 MHz, D2O): δ = 30.3 (d, JPC = 132.0 Hz, CH2-P),
40.0 (s, Ph-CH2-Ph), 122.6 (m, C-CH2-P), 131.2 (s, CH), 135.4 (t, JPC = 2.5 Hz, C-CH2),
1
151.0 (t, JPC = 6.0 Hz, C-OH). 31P{ H} NMR (109.38 MHz, D2O): δ = 25.9. MS-ESI:
[M-H]− m/z obs. 575.0065 (m/z exp. 575.0043).
{5-[4-Hydroxy-3,5-bis(phosphonomethyl)benzyl]-2-hydroxybenzyl}pho-
sphonic acid (8). The synthesis procedure used for 7 was applied also for the synthesis
of 8. Compound 4 (0.1 mol) was dissolved in trimethylphosphite (0.3 mol). The crude
ester was directly hydrolyzed. The residue was purified by HPLC (C18 column) with a
90/10 aqueous formic acid solution at pH = 3/acetonitrile mixture as eluent at a flow rate
of 3 mL/min. The product peak appeared at retention times of 68–98 min with ultraviolet
detection at 280 nm. The pure fractions were collected and concentrated under reduced
pressure to give compound 8 as a brown oil (yield 64%). IR (KBr), ν(cm−1): 1650w, broad
(POH), 1199s (P O), 1094s, 993 s, 955s (P-OH). 1H NMR (270 MHz, D2O): δ = 2.98 (d,
JPH = 20.9 Hz, 6H, CH2-P), 3.56 (s, 2H, Ph-CH2-Ph), 6.51 (d, J = 8.1 Hz, 1H, arom-H),
6.62 (s, 3H, arom-H), 6.75 (s, 1H, arom-H). 13C NMR (67.5 MHz, D2O): δ = 29.0 (d, JPC
= 132.0 Hz, CH2-P), 30.2 (d, JPC = 133.0 Hz, CH2-P), 40.0 (s, Ph-CH2-Ph), 116.7 (s,
CH); 119.9 (d, JPC = 10.5 Hz, C-CH2-P), 122.2 (dd, JPC = 9.5 Hz, 2.0 Hz, C-CH2-P),
129.2 (d, JPC = 2.0 Hz, CH), 131.2 (s, CH), 132.4 (d, JPC = 6.0 Hz, CH), 134.5 (d, JPC
=
=
2.0 Hz, C-CH2-Ph), 135.5 (s, C-CH2-Ph), 150.8 (t, JPC = 5.0 Hz, C-OH), 152.7 (d, JPC
1
6.0 Hz, C-OH). 31P{ H} NMR (109.38 MHz, D2O): δ = 26.0, 26.5. MS-ESI: [M-H]− m/z
obs. 480.8 (m/z exp. 481.03).
{[2-Hydroxy-5-(4-hydroxybenzyl)-1,3-phenylene]bis(methylene)}bispho-
sphonic acid (9) and {methylenebis[(2-hydroxy-5,1-phenylene)methylene]}
bisphosphonic acid (10). The procedure used for the synthesis of compounds 7 and 8
was applied to the mixture of 3a and 3b. The residue was purified by HPLC (C18 column)
with a 90/10 aqueous formic acid solution at pH = 3/acetonitrile mixture as eluent at a
flow rate of 2 mL/min. Two product peaks appeared at retention times from 98–126 min
and 127–140 min with ultraviolet detection at 280 nm. The pure fractions were collected
and concentrated under reduced pressure to give compounds 9 and 10 as brown solids with
65% and 25% yield, respectively.

NEW BENZYLIC DI-, TRI-, AND TETRAPHOSPHONIC ACIDS
363
Compound 9: IR (KBr), ν(cm−1): 1611w, broad (POH), 1150s (P O), 1019s, 951s
(P-OH). 1H NMR (270 MHz, D2O): δ = 2.99 (d, JPH = 20.5 Hz, 4H, CH2-P), 3.67 (s, 2H,
Ph-CH2-Ph), 6.66 (d, J = 8.1 Hz, 2H, arom-H); 6.99 (d, J = 7.8 Hz, 2H, arom-H); 6.82
(s, 2H, arom-H). 13C NMR (67.5 MHz, D2O): δ = 30.5 (d, JPC = 132.0 Hz, CH2-P), 39.9
(s, Ph-CH2-Ph), 115.7 (s, CH), 122.5 (d, JPC = 9.0 Hz, C-CH2-P), 130.4 (s, CH), 130.7
(s, CH), 134,3 (s, C-CH2-Ph), 135.3 (s, C-CH2-Ph), 150.6 (s, C-OH), 154.1 (s, C-OH).
1
31P{ H} NMR (109.38 MHz, D2O): δ = 25.3. MS-ESI: [M-H]− m/z obs. 386.8 (m/z exp.
387.05).
Compound 10: IR (KBr), ν(cm−1): 1634w, broad (POH), 1166s (P O), 1100s, 999s
(P-OH). 1H NMR (270 MHz, D2O): δ = 2.99 (d, J = 20.5 Hz, 4H, CH2-P), 3.60 (s, 2H,
Ph-CH2-Ph), 6.69 (d, J = 8.1 Hz, 2H, arom-H), 6.86 (d, J = 8.1 Hz, 2H, arom-H), 6.94
(s, 2H, arom-H). 13C NMR (67.5 MHz, D2O): δ = 30.2 (d, JPC = 132.0 Hz, CH2-P), 40.0
(s, Ph-CH2-Ph), 117.2 (s, CH), 121.2 (s, C-CH2-P), 129.0 (s, CH), 132.4 (s, CH), 135,1
1
(s, C-CH2-Ph), 152.7 (s, C-OH). 31P{ H} NMR (109.38 MHz, D2O): δ = 26.0. MS-ESI:
[M-H]− m/z obs. 386.8 (m/z exp. 387.05).
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