A study of the reaction of phosphorus trichloride with paraformaldehyde in the presence of carboxylic acids

Article abstract of DOI:10.1080/10426507.2012.745078

We investigated the mechanism of the reaction of paraformaldehyde with phosphorus trichloride in the presence of carboxylic acids (acetic, propanoic, and formic). Our results revealed that bisphosphonic acids were obtained without the use of water. The structures of the reaction products were studied by 1D and 2D homonuclear and heteronuclear ¹H-, ¹³C-, ³¹P- NMR spectroscopy. [Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional tables.]

Full text of DOI:10.1080/10426507.2012.745078

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A STUDY OF THE REACTION OF PHOSPHORUS
TRICHLORIDE WITH PARAFORMALDEHYDE IN THE
PRESENCE OF CARBOXYLIC ACIDS
K. Troev a , P. Todorov b , E. Naydenova b , V. Mitova a & N. Vassilev c
a Institute of Polymers, Bulgarian Academy of Sciences, Sofia, 1113, Bulgaria
b University of Chemical Technology and Metallurgy, Department of Organic Chemistry, Sofia,
1756, Bulgaria
c Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of
Sciences, Sofia, Bulgaria
Accepted author version posted online: 12 Dec 2012.
To cite this article: K. Troev , P. Todorov , E. Naydenova , V. Mitova & N. Vassilev (2012): A STUDY OF THE REACTION OF
PHOSPHORUS TRICHLORIDE WITH PARAFORMALDEHYDE IN THE PRESENCE OF CARBOXYLIC ACIDS, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI:10.1080/10426507.2012.745078
To link to this article: http://dx.doi.org/10.1080/10426507.2012.745078
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A STUDY OF THE REACTION OF PHOSPHORUS TRICHLORIDE WITH
PARAFORMALDEHYDE IN THE PRESENCE
OF CARBOXYLIC ACIDS
K. Troev,1* P. Todorov,2 E. Naydenova,2 V. Mitova,1 N. Vassilev3
1Institute of Polymers, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria, e-mail:
ktroev@polymer.bas.bg
2University of Chemical Technology and Metallurgy, Department of Organic Chemistry, Sofia
1756, Bulgaria, e-mail: pepi_37@abv.bg
3Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences,
Sofia, Bulgaria
O
HO
"a"
P
CH2 OH
HO
+ RCOOH
PCl3 + CH2O
O
P
R
O
P
"b"
HO
HO
OH
OH
C
R = CH3; CH3CH2; H
OH
Abstract We investigated the mechanism of the reaction of paraformaldehyde with phosphorus
trichloride in the presence of carboxylic acids (acetic, propanoic and formic). Our results
revealed that bisphosphonic acids were obtained without the use of water. The structures of the
1
reaction products were studied by 1D and 2D homonuclear and heteronuclear H-, 13C-, 31P-
NMR spectroscopy.
Keywords Hydroxymethylphosphonic acid; bisphosphonic acids; 1-hydroxyalkylidene-1,1-
diphosphonic acid; phosphorus trichloride
1
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INTRODUCTION
The reaction between phosphorus trichloride and various aldehydes (acet-, propion-,
isobutyr-, isovaler-, hept-, and benzaldehydes) to prepare α-hydroxymethylphosphonic acid
derivatives was initially studied by Fossek.1,2 α-Hydroxymethylphosphonic acid was first
synthesized by Page via the reaction of phosphorus trichloride and paraformaldehyde in a 1:1
molar ratio. Subsequent hydrolysis of the reaction product resulted in the formation of
hydroxymethylphosphonic acid in 93% yield.3 The reaction was carried out in the presence of
acetic acid. It is well known that phosphorus trichloride reacts with alkanoic acids to form the
corresponding chloro anhydrides and dichlorophosphite. Both compounds are very reactive, but
in the literature devoted to the reaction of phosphorus trichloride and paraformaldehyde in the
presence of acetic acid, the reactivity of these two compounds is not discussed. In our previous
work, we described the synthesis of new cycloalkanespiro-5-hydantoin aminophosphonic acids.4
31
It was established from the P NMR spectrum that the appearance of two signals at 20 to 22
ppm, characteristic of a phosphonic structure, could be explained by the participation of acetic
acid, used as a solvent. This was behind our interest in studying the reaction of phosphorus
trichloride with paraformaldehyde in the presence of carboxylic acids (formic, acetic and
propanoic) by NMR spectroscopy. The main goal of this study was to prove the mechanism and
structures of the reaction products.
RESULTS AND DISCUSSION
The reaction of paraformaldehyde with phosphorus trichloride in a molar ratio of 1:1 was
realized in the presence of acetic, propanoic and formic acids.
2
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In the presence of acetic acid: In the 31P{H} NMR spectrum of the reaction product
obtained by precipitation in water, there were two signals at 23.20 ppm and at 20.96 ppm. In the
3
31P NMR spectrum the signal at 23.20 ppm occurred as a triplet with a coupling constant J(P,H)
3
= 7.3 Hz, and that at 20.96 ppm was a quartet with a coupling constant J(P,H) = 16.0 Hz. In the
1H NMR spectrum of the reaction mixture there was a triplet at 1.64 ppm with a coupling
constant of 16.0 Hz and a doublet at 3.78 ppm with a coupling constant of 7.3 Hz. Also in the
1
13C{H} NMR spectrum there was a triplet at 71.6 ppm with a coupling constant of J(P,C)
=152.6 Hz and a doublet at 58.7 ppm with a coupling constant of 1J(P,C) = 162.4 Hz. There was
also a triplet at 20.7 ppm with a coupling constant of 1.4 Hz. The DEPT spectrum revealed that
the signal at 71.6 ppm was a tertiary carbon. The value of the coupling constant revealed that this
carbon atom was bonded directly to two phosphorus atoms; the triplet at 20.7 ppm was due to a
CH3 carbon atom in β-position to the phosphorus atoms. The doublet at 58.7 ppm corresponded
to a CH2 carbon, directly bonded to the phosphorus atom. Based on these data it can be assumed
that the following compounds are formed: α-hydroxymethylphosphonic acid and 1-
hydroxyethylidene-1,1-diphosphonic acid (Figure 1).
31
Based on the integral intensities of the signals in the P{H} NMR spectrum the mixture
consisted of 24% α-hydroxymethylphosphonic acid and 76% 1-hydroxyethylidene-1,1-
diphosphonic acid.
In the presence of propanoic acid: In the 31P{H} NMR spectrum of the reaction mixture,
before treating with water, there was a singlet at 20.45 ppm, a doublet (2J(P,P) = 19.2 Hz) at
19.22 ppm, singlets at 18.25 ppm, 17.88 ppm and 17.14 ppm, a doublet (2J(P,P) = 19.3 Hz) at
16.11 ppm, and singlet at 10.94 ppm, 9.79 ppm, 6.94 ppm and -2.23 ppm. In the 31P NMR
3
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3
spectrum the signal at: 20.45 ppm represents a triplet with a coupling constant J(P,H) = 8.2 Hz;
3
3
19.22 ppm, a doublet of triplets with a coupling constants J(P,P) = 19.2 Hz and J(P,H) = 16.1
2
Hz; 18.25 ppm, a triplet with a coupling constant J(P,H) = 14.3 Hz; 17.88 ppm, a triplet with
3
2
coupling constant J(P,H) = 9.1 Hz; 17.14 ppm, a triplet with a coupling constant J(P,H) = 14.3
2
3
Hz; 16.11 ppm, a doublet of triplets with coupling constants J(P,P) = 19.3 Hz and J(P,H) =
3
14.1 Hz; 10.94 ppm, a doublet of quartets with a coupling constants J(P,H) = 3.2 and 11.7 Hz;
3
9.79 ppm, a doublet with a coupling constant J(P,H) = 9.8 Hz; 6.96 ppm, a doublet of quartets
with a coupling constants of 3.2 and 10.2 Hz. The signal at -2.23 ppm represents a singlet and
can be assigned to the phosphorus atom in trichlorophosphate. This compound can be obtained
as a result of oxidation of phosphorus trichloride.
31
In the P NMR spectrum of the reaction mixture, obtained after addition of water, there were
three signals present: a triplet with a coupling constant of 7.2 Hz at 23.5 ppm, a triplet with a
coupling constant of 15.7 Hz at 21.4 ppm and a doublet with a coupling constant 1J(P,H) = 668.8
Hz at 4.85 ppm. The signals at: 19.3, 18.3, 17.9, 17.2, 16.1, 10.9, 9.7, and 6.9 ppm disappeared
after adding of water. The new signal at 4.85 ppm represents a doublet with a coupling constant
1J(P,H) = 668.8 Hz assigned to the phosphorus atom in the H-phosphonic acid. The H-
phosphonic acid is formed after treating the reaction mixture with H2O. Obviously, hydrolysis of
a four coordinated phosphorus compound resulted in the formation of the H-phosphonic acid
31
because in the P{H} NMR spectrum of the reaction mixture before adding water there was no
signal in the region 200 - 220 ppm, characteristic of a trivalent phosphorus atom, including the
phosphorus atom of phosphorus trichloride, and there was no signal at 4.85 ppm. The only
compound, which can be converted via hydrolysis in a H-phosphonic acid, is dichloro H-
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phosphonate. According to the integral intensity of the phosphorus atoms in the reaction mixture,
the content of H-phosphonic acid was 42%.
The triplet at 1.16 ppm with coupling a constant of 7.6 Hz in the 1H NMR of the reaction
mixture can be assigned based by HSQC to a CH3 in the fragment -CH2-CH3. The DEPT
spectrum revealed that the signal was also due to the CH3 carbon. The doublet at 3.77 ppm with a
coupling constant of 7.4 Hz based on the HSQC spectrum was assigned to the CH2 protons in the
fragment, P-CH2OH. The DEPT spectrum confirmed this inference. The multiplet at 2.09 ppm
3
(triplet of quartets with a coupling constants 3J(H,H) = 7.6 and J(P,H) = 15.8 Hz) was assigned
to the CH2 protons in the fragment [P-C- (CH2-CH3)-P]; the HSQC spectrum revealed that this
signal correlated with the CH2 signal at 27.89 ppm in the 13C{H} NMR spectrum and can be
assigned to the CH2 carbon atom in β-position to the phosphorus atom (In the literature a 2J(P,C)
constant close to 0 Hz in phosphonates has been reported5). In the 13C{H} NMR spectrum there
was a triplet at 74.5 ppm with a coupling constant of 148.3 Hz and a doublet at 58.2 ppm with a
coupling constant of 162.8 Hz. There was a triplet at 8.77 ppm with a coupling constant of 6.4
Hz. The DEPT spectrum revealed that the signal at 74.5 ppm was a tertiary carbon atom; that at
58.2 ppm was due to a CH2 carbon, and the signal at 27.8 ppm was also due to a CH2 carbon.
The triplet at 8.77 ppm is due to the CH3 carbon atom. The values of the coupling constants for
the triplet and doublet revealed that these carbon atoms were directly connected to the
phosphorus atom.
NMR data supported the formation of the following two compounds during the reaction
between phosphorus trichloride and paraformaldehyde in the presence of propanoic acid: α-
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hydroxymethylphosphonic acid (Figure 1a) and 1-hydroxypropylidene-1,1-diphosphonic acid
(Figure 2).
The content of α-hydroxymethylphosphonic acid was 35% and that of 1-
hydroxypropylidene-1,1-diphosphonic acid was 65% based on the integral intensities of the
signal for phosphorus atoms in the 31P{H} NMR spectrum.
In the presence of formic acid: The reaction of phosphorus trichloride with
paraformaldehyde in the presence of formic acid resulted in the formation of two phosphorus-
containing products. The 31P NMR spectrum of the reaction mixture revealed two types of
phosphorus atoms at 23.23 ppm, a triplet with a coupling constant of 7.2 Hz and at 16.78 ppm, a
pseudo-triplet with a coupling constant of 9.1 Hz. The contents of the products were 89% and
1
11%, respectively. The doublet at 3.76 ppm in the H NMR spectrum was assigned to the P-CH2
protons. The DEPT spectrum confirmed that these protons were bonded to this carbon atom. In
the 13C {1H} NMR spectrum there was a doublet at 58.2 ppm with a coupling constant of 1J(P,C)
= 161.7 Hz, which was characteristic of a carbon atom bonded directly to phosphorus.
NMR data confirmed the formation of α-hydroxymethylphosphonic acid and 1-
hydroxymethylene-1,1-diphosphonic acid (Figure 3).
Based on the data from NMR studies we propose the following mechanism for the
reaction of phosphorus trichloride with paraformaldehyde in the presence of carboxylic acids
(Scheme 1). The reaction proceeds in two directions: pathway “a” and pathway “b”. In pathway
“a” phosphorus trichloride reacts with formaldehyde to form chloromethyl dichlorophosphite (2)
which undergoes an Arbuzov rearrangement to give chloromethyl dichorophosphonate (3).
Hydrolysis of 3 resulted in α-hydroxymethylphosphonic acid 4. At the same time phosphorus
6
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trichloride reacts with the carboxylic acid to furnish the corresponding acid chloride 5 and
dichlorophosphite (6). Dichorophosphite tautomerizes in to dichloro H-phosphonate (7) which
reacts with acid chloride 5 to give dichloro acylphosphonate 8.
The addition of dichloro H-phosphonate 7 to 8 furnished the tetrachloride of 1-
hydroxyalkylidene-1,1-diphosphonic acid 9. Hydrolysis of 9 resulted in the formation of 1-
hydroxyalkilidene-1,1-diphosphonic acid 10. This reaction scheme explains the observed signals
in the 31P NMR spectrum of the reaction mixture before adding water. The singlets at 20.45 ppm,
18.22 ppm, 17.88 ppm and 17.14 ppm can be assigned to dichlorochloromethyl phosphonic acid
(3), partially hydrolyzed 3, dichloro acylphosphonate 8 and partially hydrolyzed 8. It is well
known that 1-hydroxyalkylidene-1,1-diphosphonic acid can be obtained by reaction of acylating
agents with H-phosphonic acid or a carboxylic acid with phosphorus trichloride and a calculated
amount of water.6-11 When phosphorus trichloride is used water is added in order to obtain the H-
phosphonic acid, which further reacts with acid anhydride. Our experimental results revealed that
the reaction of phosphorus trichloride with paraformaldehyde in the presence of carboxylic acids
in the absence of water resulted in the formation of 1-hydroxyalkylidene-1,1-diphosphonic acids.
Interaction of phosphorus trichloride with glacial acetic acid
We also carried out the reaction of phosphorus trichloride with glacial acetic acid. In the
31P{H} NMR spectrum of the reaction mixture there were four signals at 20.43, 16.54, 15.97 and
31
5.66 ppm. The signal at 20.43 ppm in the P NMR spectrum represents a quartet with coupling
3
3
constant J(P,H) = 16.1 Hz, that at 16.54 ppm is a quartet with a coupling constant J(P,H) =
15.4 Hz and that at 15.97 ppm is a quartet with a coupling constant 3J(P,H) = 15.5 Hz. The signal
1
at 5.66 represents a doublet with a coupling constant J(P,H) = 680.9 Hz which is characteristic
7
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1
for J(P,H) hence this doublet can be assigned to the H-phosphonic acid. According to the
integral intensity of the signals at 20.43, 16.54, 15.97 and 5.66 ppm the content of the product
1
mixture was 18%, 7%, 7% and 68% respectively. In the H NMR spectrum of the reaction
3
mixture there was a triplet at 1.12 ppm with a coupling constant J(P,H) = 16.3 Hz which was
assigned to the CH3 protons, split by two phosphorus atoms. There were also two doublets at
1.57 (3J(P,H) = 16 Hz) ppm and 6.39 (1J(P,H) = 680.8 Hz) ppm. This coupling constant is
characteristic for a P-H proton. In the 13C{H} NMR spectrum there were a triplets at 69.4
1
(1J(P,C) = 152.6 Hz) ppm and at 78.1 ppm with a coupling constant J(P,C) = 147.1 Hz of
extremely low intensity. The DEPT spectrum revealed that these signals were due to tertiary
carbon atoms. The values of the coupling constants revealed that these carbon atoms were
bonded directly to two phosphorus atoms and the triplet at 69.4 ppm could be assigned to the
tertiary carbon atom of 1-hydroxyethylidene-1,1-diphosphonic acid (11).
Additional signals in 13C and in 31P NMR spectra can be explained by the formation of a
13
conformer of 11 with intramolecular hydrogen bonding. The triplet at 78.1 ppm C{H} NMR
spectrum with a coupling constant J(P,C) = 147.1 Hz is shielded to lower field. The quartets at
31
16.54 and 15.97 ppm (for two non-equivalent phosphorus of the H-bonded 11) in P{H} NMR
spectrum are supporting this suggestion too.
NMR data confirmed that the reaction of phosphorus trichloride with glacial acetic acid
resulted in formation of 1-hydroxyethylidene-1,1-diphosphonic acid 11.
The transformation of dichlorophosphite (6) into dichloro H-phosphonate (7) was
confirmed by NMR study of the reaction mixture, PCl3 and H2O (large excess of PCl3). The
31P{H} NMR spectrum of the reaction mixture showed a signal at 220.29 ppm (intensity 100.0),
8
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10.81 ppm (intensity 4.51) and at -2.19 ppm (intensity 16.49). In the 31P NMR spectrum the
signal at 220.29 ppm was a singlet and was assigned to phosphorus atom in PCl3; that at 10.81
ppm was a doublet with a coupling constant of 737.4 Hz and was assigned to the phosphorus
atom in chlorohydroxy H-phosphonate. In ACD Labs software12 1J(P,H) constant for
chlorohydroxy H-phosphonate is 748.5 Hz. The signal at –2.19 ppm is a doublet with a coupling
constant of 777.5 Hz and can be assigned to phosphorus atom in dichloro H-phosphonate (7). In
1
the database of ACD Labs software12 it was found that the J(P,H) constant for dichloro H-
1
phosphonate was 772.0 Hz. In the H NMR spectrum of the same mixture, there were two
1
doublets at 7.23 ppm with J(P,H) = 781.4 Hz assigned to the P-H proton in dichloro H-
1
phosphonate (7) and at 7.07 ppm with J(P,H) =735.9 Hz assigned to the P-H proton of
chlorohydroxyl-H-phosphonate. There was a broad signal at 11.9-13.1 ppm assigned to the
proton of the P-OH group. These data confirmed that under the reaction conditions,
dichlorophosphite (6) tautomerized into dichloro H-phosphonate. The equilibrium was shifted to
dichloro H-phosphonate (7). There was no other signal due to a trivalent phosphorus atom except
for the phosphorus atom of PCl3 at 220.29 ppm.
CONCLUSION
In conclusion, it was shown that the carboxylic acid used in the reaction of PCl3 with
parafomaldehyde plays the dual role of solvent and reagent. The carboxylic acid cannot be used
as the solvent in the reaction of PCl3 with parafomaldehyde for the preparation of α-
hydroxymethylphosphonic acid because it reacts with PCl3. Our results have revealed that
bisphosphonic acids can be obtained from carboxylic acids and PCl3 without the addition of
water. The dichlorophosphite obtained from the reaction of the carboxylic acid and PCl3
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generates dichloro H-phosphonate, the reagent which reacts with the acid chloride to give an
acylphosphonate, and it addition to acylphosphonate furnished the resulting tetrachloride of 1-
hydroxyalkylidene-1,1-diphosphonic acid.
EXPERIMENTAL
Instruments and Reagents
All reagents were used as purchased from commercial suppliers without further
purification. Solvents were dried and purified by conventional methods prior to use. We used
glacial acetic acid ≥99.99%; propionic acid ≥99.5%; formic acid ≥96.0 % from Sigma-Aldrich.
13
31
1H, C and P spectra were recorded on Bruker DRX 250 spectrometer using QNP probehead
1
and on Bruker Avance II+ 600 spectrometer using BBO probehead. The H and 13C NMR
31
chemical shifts are given relative to TMS, while the P NMR chemical shifts are given relative
to 85% H3PO4. Chemical shifts are expressed in ppm and coupling constants in Hz. The precise
1
assignment of the H and 13C NMR spectra was accomplished by measurement of 2D
homonuclear correlation (COSY), DEPT-135 and 2D inverse detected heteronuclear (C–H)
1
correlations (HMQC and HMBC). Sample H, 13C and 31P NMR spectra from reactions are
found in the Supplemental Materials (Figures S 1 – S 12)
General Procedure of the Reaction of Phosphorus Trichloride with
Paraformaldehyde in the Presence of Carboxylic Acids.
Paraformaldehyde (1.50 g, 0.05 mol) and glacial acetic acid (24 mL) were added to a
four-necked round–bottom flask equipped with a magnetic stirbar, reflux condenser,
thermometer, dropping funnel and argon inlet. A white suspension formed. The mixture was
o
refluxed (approximately 115 C) for 2 h, after which it became a clear solution. The temperature
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was lowered to 20 oC and PCl3 (4.20 mL, 0.05 mol) was added dropwise. For the whole duration
of the reflux (6 h) during and after the addition of PCl3, hydrogen chloride was evolved. After 6
h refluxed, the reaction was stopped, and the mixture was analyzed by NMR spectroscopy. After
that tо this reaction mixture was added distilled water (28 mL) and refluxed again for 2.5 h. After
2.5 h refluxing the solvent was removed in vacuo to give a yellow tarry residue. This residue was
dissolved in and filtered over activated carbon is used in methanol purification resulting a
colorless solution. Then the solution was concentrated under reduced pressure to give a residue,
which was purified by precipitation from water and collected by filtration.
Analytical data:
In the presence of:
1
3
a) Acetic acid: H NMR (600 MHz, CD3ОD) δ (ppm): 1.64 (t, J(P,H) = 16.0 Hz, P -
2
13
C(CH3)-P); 3.78 (d, J(P,H) = 7.3 Hz, P-CH2-OH); C {1H} NMR (150 MHz, CD3ОD) δ
1
1
(ppm): 71.66 (t, J(P,C) = 152.6 Hz, (P-C-P); 58.73 (d, J(P,C) = 162.4 Hz, P-CH2-), 20.77
(t, 3J(P,H) = 1.4 Hz, P-C(CH3)-P); 31P NMR (243 MHz, CD3ОD) δ (ppm): 20.96 (q, 3J(P,H)
= 16.0 Hz); 23.20 (t, 2J(P,H) = 7.3 Hz).
b) Propanoic acid: 1H NMR (600 MHz, CD3ОD) δ (ppm): 1.16 (t, 3J(H,H) = 7.6 Hz, -CH2-
2
3
3
CH3); 3.76 (d, J(P,H) = 7.25 Hz, P-CH2-OH), 2.09 (tq, J(P,H) = 15.2 Hz, J(H,H) = 7.6
13
1
Hz, P-C- (CH2-CH3)-P); C {1H} NMR (150 MHz, CD3ОD) δ (ppm): 74.55 (t, J(P,C) =
1
153.9 Hz, P-C-P); 58.25 (d, J(P,C) = 162.0 Hz, P-CH2-); 27.89 [P-C- (CH2-CH3)-P]; 8.77
3
(t, J(P,C) = 6.0 Hz [P-C- (CH2-CH3)-P]; 31P NMR (243 MHz, CD3ОD) δ (ppm): 21.43 (t,
3J(P,H) = 15.7 Hz); 23.56 (t, 2J(P,H) = 7.2 Hz).
11
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c) Formic acid: 1H NMR (600 MHz, CD3ОD) δ (ppm): 3.76 (d, 2J(P,H) = 7.25 Hz, P-CH2-
1
); 13C {1H} NMR (150 MHz, CD3ОD) δ (ppm): 58.20 (d, J(P,C) = 162.9 Hz, P-CH2-); 31P
NMR (243 MHz, CD3ОD) δ (ppm): 23.23 (t, 2J(P,H) = 7.1 Hz); 16.78 (t, 2J(P,H) = 9.1 Hz).
ACKNOWLEDGEMENTS
Financial support of this work was provided by the National Science Fund of Bulgaria
(National Center for Advanced Materials (UNION) Module 2 “New materials in medicine and
pharmacy” Contract № DCVP 02-2 /2009, Grant DPOSTDOC 02/3, Grant DTK 02/61, and
Grant UNA-17/2005. We wish to thank COST ACTION CM 0802-PhoSciNet.
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2. Fossek, W. Monutsh. 1886, 7, 20-39.
3. Page, H. J. J. Chem. Soc. Trans. 1912, 101, 423-431.
4. Naydenova, E.; Todorov, P.; Troev, K. Phosphorus, Sulfur, Silicon Relat. Elem. 2010,185,
1315-1320.
5. Quin, L. D.; Borleske, S. G.; Stocks, R. C. Org. Magn. Reson. 1973, 5, 161-162.
6. Blaser, Von B.; Worms, K. H.; Gremschied, H. G.; Wollmann, K. Z. Anorg. Allg. Chem.
1971, 381, 247-259.
7. Blum, H.; Worms, K.H. D.E. Patent 3,016,289, 1981.
8. Blum, H.;Hempel, H.U.;Worms, K.H. U.S. Patent 4,267,108, 1981.
9. Staibano G. G.B. Patent 2,166,741, 1986.
10. Kieczykowski, G. R.; Jobson, R. B.; Melillo, D. G.; Reinhold, D. E.; Grenada, V. J.;
Shinkai, I. J. Org. Chem. 1995, 60, 8310-8312.
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11. Xie, Y.; Ding, H.; Qian, L.; Yan, X.; Yang, C.; Xie, Y. Biorg. Med. Chem. Lett. 2005, 15,
3267-3270.
12. ACD Labs software. NMR Predictor Suite. Advanced Chemistry Development Inc. 110
Yonge Street, 14th Floor, Toronto, Ontario, Canada M5C 1T4.
O
P
O
P
CH3
C
O
P
b)
a)
HO
HO
HO
HO
OH
OH
CH2 OH
OH
Figure 1. a) α-Hydroxymethylphosphonic acid and b) 1-hydroxyethylidene-1,1-diphosphonic
acid
CH3
O
P
O
P
CH2
C
HO
HO
OH
OH
OH
Figure 2. Structure of 1-hydroxypropylidene-1,1-diphosphonic acid
O
P
H
O
P
HO
HO
OH
OH
C
OH
Figure 3. Structure of 1-hydroxymethylene-1,1-diphosphonic acid
13
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O
P
O
P
Cl
Cl
Cl
HO
HO
H2O
a
P
O CH2 Cl
CH2 Cl
CH2 OH
Cl
3
4
+ RCOOH
2
PCl3 + CH2O
O
1
b
+
R
C
Cl
HOPCl2
R = CH3; CH3CH2; H
5
6
O
R
C
O
O
Cl
Cl
Cl
Cl
P
O
O
R
C
Cl
+
P H
8
5
7
Cl
Cl
P H
+
7
O
P
R
O
Cl
Cl
Cl
Cl
C
P
9
OH
H O
+
2
O
R
O
P
HO
HO
OH
OH
P
C
OH
10
Scheme 1. Reaction of phosphorus trichloride with paraformaldehyde in the presence of
carboxylic acids.
14
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
O
+
+
HOPCl2
CH3COOH
PCl3
H3C
C
Cl
6
O
P
CH3
C
O
O
C
Cl
Cl
Cl
Cl
O
H
H C
Cl
+
H
P
3
7
O
Cl
Cl
P
+
7
O
P
CH3
O
P
O
P
CH3
C
O
P
HO
HO
Cl
Cl
OH
OH
Cl
Cl
H2O
+
C
OH
OH
11
Scheme 2. Reaction of phosphorus trichloride with glacial acetic acid.
15
ACCEPTED MANUSCRIPT