Investigations into the oxidative stability of hydroxymethyl- and bis(hydroxymethyl)-phosphines

Article abstract of DOI:10.1080/10426500701761417

Polydentate ligands containing the bis(hydroxymethyl)phosphine unit have been reported to exhibit enhanced oxidative stability, which would make them attractive for use in 99mTc-radiopharmaceutical imaging agents. Benzylethyl(hydroxymethyl)phosphine, benzylbis(hydroxymethyl)phosphine and benzyldiethylphosphine were prepared in order to investigate the origin of this oxidative stability. Little evidence was found to indicate that the hydroxymethylphosphines show an enhanced level of stability, but it was demonstrated that the reaction conditions employed in their preparation generated a number of closely related by-products, which are likely to limit the usefulness of the hydroxymethylphosphines in commercial radiopharmaceutical applications. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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Investigations into the
Oxidative Stability of
Hydroxymethyl- and
Bis(Hydroxymethyl)-Phosphines
D. V. Griffiths a , H. J. Groombridge a & M. C. Salt a
a School of Biological and Chemical Sciences ,
Queen Mary, University of London , London, United
Kingdom
Published online: 20 Jun 2008.
To cite this article: D. V. Griffiths , H. J. Groombridge & M. C. Salt (2008)
Investigations into the Oxidative Stability of Hydroxymethyl- and Bis(Hydroxymethyl)-
Phosphines, Phosphorus, Sulfur, and Silicon and the Related Elements, 183:2-3,
473-478, DOI: 10.1080/10426500701761417
To link to this article: http://dx.doi.org/10.1080/10426500701761417
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Phosphorus, Sulfur, and Silicon, 183:473–478, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701761417
Investigations into the Oxidative Stability
of Hydroxymethyl- and Bis(Hydroxymethyl)-Phosphines
D. V. Griffiths, H. J. Groombridge, and M. C. Salt
School of Biological and Chemical Sciences, Queen Mary, University
of London, London, United Kingdom
Polydentate ligands containing the bis(hydroxymethyl)phosphine unit have been re-
ported to exhibit enhanced oxidative stability, which would make them attractive for
use in 99m Tc-radiopharmaceutical imaging agents. Benzylethyl(hydroxymethyl)-
phosphine, benzylbis(hydroxymethyl)phosphine and benzyldiethylphosphine were
prepared in order to investigate the origin of this oxidative stability. Little evidence
was found to indicate that the hydroxymethylphosphines show an enhanced level
of stability, but it was demonstrated that the reaction conditions employed in their
preparation generated a number of closely related by-products, which are likely to
limit the usefulness of the hydroxymethylphosphines in commercial radiopharma-
ceutical applications.
Keywords
Hydroxymethylphosphine;
Oxidation;
Stability;
Tc-99m
Radiopharmaceuticals
INTRODUCTION
As part of an ongoing programme to develop new ligands for
technetium-99m based radiopharmaceutical imaging agents, we have
investigated the potential for utilising the bis(hydroxymethyl)phos-
phine group as a means of producing more hydrophilic, air stable
phosphine-containing ligands.
In particular, we have investigated the preparation of ben-
zyldiethylphosphine 1, benzylethyl(hydroxymethyl)phosphine 2 and
benzylbis (hydroxymethyl)phosphine 3 as model systems for evaluat-
ing claims that chelate systems containing the bis(hydroxymethyl)-
phosphine unit display enhanced oxidative stability1 (Scheme 1).
The authors wish to thank the EPSRC for financial support for HJG. They also wish
to thank M. Motevalli for obtaining the X-ray crystallography data.
Address correspondence to D. V. Griffiths, School of Biological and Chemical
Sciences, Queen Mary, University of London, London E1 4NS, United Kingdom.
E-mail: d.v.griffiths@qmul.ac.uk
473

474
D. V. Griffiths et al.
P
P
OH
P
OH
OH
3
1
2
SCHEME 1
RESULTS AND DISCUSSION
Benzylethyl(hydroxymethyl)phosphine 2 was synthesised using the ap-
proach established by Katti.2 However, the reaction of benzylethylphos-
phine 4 with formaldehyde (Scheme 2) generated not only the de-
sired product 2, but also the corresponding phosphonium salt 5 and
the phosphine oxide 6. Moreover, the hydroxymethylphosphine 2 was
found to convert to the corresponding phosphine oxide 6 even when
operating under an inert atmosphere, thereby demonstrating that
the mono(hydroxymethyl)phosphine 2 does not exhibit high oxidative
stability.
SCHEME 23
We subsequently investigated the oxidative stability of benzyl-
bis(hydroxymethyl)phosphine 3. While treatment of benzylphosphine
7 with aqueous formaldehyde gave the bis(hydroxymethyl)phosphine 3
as the main product, four other products were also observed and iden-
tified as the hemiacetals 8 and 9, the phosphonium salt 10 and the
phosphine oxide 11 (Scheme 3).
Due to difficulties experienced in isolating the products from the re-
action mixture, it was thought prudent to investigate an alternative
approach for the preparation of benzylbis(hydroxymethyl)phosphine 3.
Based on Vullo’s observation4 that tris(hydroxymethyl)phosphine 13

Hydroxymethyl- and Bis(Hydroxymethyl)-Phosphines
475
SCHEME 3
could be prepared by exact neutralisation of tetrakis(hydroxymethyl)
phosphonium chloride 12, Petrov developed a method to prepare a series
of alkyl- and aryl-(hydroxymethyl)phosphines by reaction of their cor-
responding phosphonium salt with triethylamine.5 We therefore inves-
tigated this approach (Scheme 4). Interestingly the same by-products
(8–11) were again observed in this reaction.
SCHEME 4
In order to facilitate purification, the hydroxymethylphosphines 3,
8 and 9 were converted to their phosphine sulfide derivatives. Benzyl-
bis(hydroxymethyl)phosphine sulfide 14 was successfully isolated as
colourless crystals suitable for analysis by single crystal X-ray crystal-
lography, (the structure is shown in Figure 1).6 Reduction of the phos-
phine sulfide 14 afforded benzylbis(hydroxymethyl)phosphine 3 in a
pure state.

476
D. V. Griffiths et al.
FIGURE 1 ORTEP view of benzylbis(hydroxymethyl)phosphine sulfide (14).
Further investigation of the bis(hydroxymethyl)phosphine 3 con-
firmed that it not only readily oxidised on exposure to air, but would
react with formaldehyde to give the hemiacetal derivatives 8 and
9. Work is still ongoing to isolate pure samples of the hemiacetal
derivatives.
CONCLUSION
It is clear that the simple hydroxymethylphosphines that we have pre-
pared do not exhibit unusually high oxidative stability. We must there-
fore conclude that the previously reported1 oxidative stability of the
hydroxymethylphosphine-containing polydentate ligands results from
a stabilising influence of the overall structure of these systems rather
than the intrinsic stability of the hydroxymethylphosphine unit. In ad-
dition, the synthesis of hydroxymethylphosphines via the routes de-
scribed are complicated by the formation of hemiacetal derivatives with
the consequence that hydroxymethylphosphine chelates are unlikely to
be attractive for use in radiopharmaceutical imaging agents where the
ligands are required in high levels of purity.
EXPERIMENTAL
Preparation of Hydroxymethylphosphines
via Katti’s Method1
The parent phosphine (4 or 7) was carefully added to a freshly pre-
pared, degassed solution of 37% aqueous formaldehyde. The reaction
mixture was stirred under an atmosphere of anhydrous argon for 1 h

Hydroxymethyl- and Bis(Hydroxymethyl)-Phosphines
477
at room temperature and formation of the required product confirmed
by NMR spectroscopy.7
via Petrov’s Method 5
The parent phosphonium salt (5 or 10) was added to an excess of
anhydrous triethylamine. The resulting solution was heated at 60◦C,
under an atmosphere of anhydrous argon, with vigorous stirring for
3 h. After this time, the solution was cooled to room temperature and the
unwanted triethylamine hydrochloride salt was removed by filtration.
The remaining triethylamine solvent was removed from the filtrate by
distillation at atmospheric pressure and formation of the required prod-
uct was confirmed by NMR spectroscopy.
Benzylbis(hydroxymethyl)phosphine 3
Sulfur was added to
a
solution of the crude benzyl-
bis(hydroxymethyl)phosphine in anhydrous benzene and the reaction
mixture was heated under reflux in an atmosphere of anhydrous
argon, for 24 h. After this time, the solution was cooled, filtered and
the solvent was removed under reduced pressure. The resulting dark
red oil was purified by flash chromatography on silica eluting with
a solvent gradient of 100% hexane to 100% ethyl acetate. A sample
of benzylbis(hydroxymethyl)phosphine sulfide 14, suitable for single
crystal X-ray crystallography was obtained by recrystalisation from
ethyl acetate.8 A pure sample of benzylbis(hydroxymethyl)phosphine
3 was obtained by reduction of the corresponding phosphine sulfide
with lithium aluminium hydride in anhydrous 1,4-dioxane.
REFERENCES
[1] K. V. Katti, K. Raghuraman, N. Pillarsetty, W. A. Volkert, S. S. Jurisson, and T. J.
Hoffman, Technetium, Rhenium and Other Metals in Chemistry and Nuclear
Medicine 6; M. Nicolini, G. Bandoli, and U. Mazzi, Eds. (SGE Editorali, Padova,
Italy, 2002), pp. 69–72.
[2] K. V. Katti, H. Gali, C. J. Smith, and D. E. Berning, Acc. Chem. Res., 32, 9 (1999).
[3] 31P NMR chemical shifts are quoted relative to an 85% solution of phosphoric acid
in D2O, as an external reference. The % yields are 31P NMR integration %.
[4] W. J. Vullo, J. Org. Chem., 33, 3665 (1968).
[5] K. A. Petrov, V. A. Parshina, and M. B. Luzanova, J. Gen. Chem. USSR, 32, 542 (1962).
[6] X-ray crystallography data was collected at 120 K using a Nonius Kappa CCD area
detector diffractometer mounted at the window of a molybdenum rotating anode
˚
(50 KV, 90 mA, λ = 0.71069 A). The crystal-to-detector distance was 30 mm and φ
and ꢀ scans (1.0◦ increments, 20 s exposure time) were carried out to fill the Ewald
sphere. Data collection and processing were carried out using COLLECT, DENZO and
maXus and empirical absorption correction was applied using SORTAV. The structure
was solved by the heavy-atom method using DIRDIF-99 and refined anisotropically

478
D. V. Griffiths et al.
(non-hydrogen atoms) by full-matrix least-squares on F2 using the SHELXL-97 pro-
gram. The H atoms were calculated geometrically and refined with the riding model.
The programs ORTEP-3 and PLATON were used for drawing the molecule. WINGX
was used to prepare material for publication.
[7] 31P NMRꢀRspectra were recorded on a JEOL EX 270 with the sample in an evacuated
WILMAD NMR tube with a J. Young valve.
[8] The data have been deposited with the Cambridge Crystallographic Data Center as
CCDC 676677; available online at: http://www.ccdc.cam.ac.uk/data request/cif