Methylene-bis[(aminomethyl)phosphinic acids]: Synthesis, acid-base and coordination properties

Article abstract of DOI:10.1039/c2dt32045b

Three symmetrical methylene-bis[(aminomethyl)phosphinic acids] bearing different substituents on the central carbon atom, (NH₂CH ₂)PO₂H-C(R¹)(R²)-PO ₂H(CH₂NH₂) where R¹ = OH, R ² = Me (H₂L¹), R¹ = OH, R ² = Ph (H₂L²) and R¹,R² = H (H₂L³), were synthesized. Acid-base and complexing properties of the ligands were studied in solution as well as in the solid state. The ligands show unusually high basicity of the nitrogen atoms (log K₁ = 9.5-10, log K₂ = 8.5-9) if compared with simple (aminomethyl)phosphinic acids and, consequently, high stability constants of the complexes with studied divalent metal ions. The study showed the important role of the hydroxo group attached to the central carbon atom of the geminal bis(phosphinate) moiety. Deprotonation of the hydroxo group yields the alcoholate anion which tends to play the role of a bridging ligand and induces formation of polynuclear complexes. Solid-state structures of complexes [H ₂NC(NH₂)₂][Cu₂(H_-1L ²)₂]CO₃·10H₂O and Li ₂[Co₄(H_-1L¹)₃(OH)] ·17.5H₂O were determined by X-ray diffraction. The complexes show unexpected geometries forming dinuclear and cubane-like structures, respectively. The dinuclear copper(ii) complex contains a bridging μ₂-alcoholate group with the ^-O-P(O)-CH ₂-NH₂ fragments of each ligand molecule chelated to the different central ion. In the cubane cobalt(ii) complex, one μ₃-hydroxide and three μ₃-alcoholate anions are located in the cube vertices and both phosphinate groups of one ligand molecule are chelating the same cobalt(ii) ion while each of its amino groups are bound to different neighbouring metal ions. All such three metal ions are bridged by the alcoholate group of a given ligand.

Full text of DOI:10.1039/c2dt32045b

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Methylene-bis[(aminomethyl)phosphinic acids]:
synthesis, acid–base and coordination properties†
Cite this: Dalton Trans., 2013, 42, 2414
Tomáš David, Soňa Procházková, Jana Havlíčková, Jan Kotek, Vojtěch Kubíček,*
Petr Hermann and Ivan Lukeš
Three symmetrical methylene-bis[(aminomethyl)phosphinic acids] bearing different substituents on the
central carbon atom, (NH2CH2)PO2H–C(R1)(R2)–PO2H(CH2NH2) where R1 = OH, R2 = Me (H2L1), R1 = OH,
R2 = Ph (H2L2) and R1,R2 = H (H2L3), were synthesized. Acid–base and complexing properties of the
ligands were studied in solution as well as in the solid state. The ligands show unusually high basicity of
the nitrogen atoms (log K1 = 9.5–10, log K2 = 8.5–9) if compared with simple (aminomethyl)phosphinic
acids and, consequently, high stability constants of the complexes with studied divalent metal ions. The
study showed the important role of the hydroxo group attached to the central carbon atom of the
geminal bis(phosphinate) moiety. Deprotonation of the hydroxo group yields the alcoholate anion
which tends to play the role of a bridging ligand and induces formation of polynuclear complexes. Solid-
state structures of complexes [H2NvC(NH2)2][Cu2(H−1L2)2]CO3·10H2O and Li2[Co4(H−1L1)3(OH)]·17.5H2O
were determined by X-ray diffraction. The complexes show unexpected geometries forming dinuclear
and cubane-like structures, respectively. The dinuclear copper(II) complex contains a bridging μ2-alcoho-
late group with the −O–P(vO)–CH2–NH2 fragments of each ligand molecule chelated to the different
central ion. In the cubane cobalt(II) complex, one μ3-hydroxide and three μ3-alcoholate anions are
located in the cube vertices and both phosphinate groups of one ligand molecule are chelating the same
cobalt(II) ion while each of its amino groups are bound to different neighbouring metal ions. All such
three metal ions are bridged by the alcoholate group of a given ligand.
Received 4th September 2012,
Accepted 14th November 2012
DOI: 10.1039/c2dt32045b
www.rsc.org/dalton
atom in the side chain attached to the bridging carbon atom
inhibit farnesyl diphosphate synthase.3 The BPs without the
Introduction
Aminoalkylphosphonic and -phosphinic acids represent a nitrogen atom are metabolized into non-hydrolysable methyl-
group of organophosphorus compounds with a wide range of ene-containing ATP analogues, which are accumulated inside
applications.1–3 A specific group of compounds among amino- the cell and exhibit cytotoxicity.4 Unfortunately, the BP’s cyto-
alkylphosphonates are those containing the geminal bis- toxicity and inhibition activity cannot be used for other than
(phosphonic acid) group. The geminal bis(phosphonic acids) bone-associated applications due to the extremely strong
(BPs) exhibit high affinity to hydroxyapatite, the main in- affinity of BPs to calcified tissues.5 An alternative could be
organic component of bone tissue, and they are regularly found in geminal bis(phosphinates), BPis. The geminal bis-
applied as drugs for treatment of osteoporosis, Paget’s disease (phosphinates) maintain the P–C–P fragment and show low
and other disorders of calcified tissues metabolism. They are affinity to hydroxyapatite.6,7 Whereas geminal BPs have been
engaged not only in protection of the bone surface, but also in widely studied, geminal BPis have attracted much less atten-
growth regulation of cells which are responsible for bone for- tion. Some of them have been synthesized6–11 but there have
mation and resorption. The geminal BPs containing a nitrogen been published only a few papers dealing with their coordi-
nation behaviour12,13 except for two simple ligands, methyl-
ene-bis(phosphinic acid), where phosphorus is directly bound
Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague,
to Pt(II) or Pd(II),14 and methylene-bis[(phenyl)phosphinic
Hlavova 2030128 40 Prague 2, Czech Republic. E-mail: kubicek@natur.cuni.cz;
acid] H2pcpPh (Scheme 1).15
Fax: +420 221921253; Tel: +420 221921264
†Electronic supplementary information (ESI) available: Overall protonation con-
However, amine-containing geminal BPis offer various
coordination modes and, thus, we turned our attention to the
stants and stability constants; distribution diagrams of H2L2 and H2L3; HR-MS
spectra of Cu-L1 and Cu-L2 systems; geometrical parameters of the bis(phosphi-
synthesis and characterization of methylene-bis[(amino-
nate) moiety and coordination spheres in the solid state. CCDC 898276, 898277,
898278 and 898279. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2dt32045b
methyl)phosphinic acids]. Here, we report on results of the
study of the symmetrical ligands bearing different substituents
2414 | Dalton Trans., 2013, 42, 2414–2422
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amount of water and left standing overnight. A white crystal-
line solid was collected by filtration on a glass frit, washed
with cold water and dried in a desiccator over P2O5 to give the
product (17.2 g, 31%).
2
3
NMR (dmso-d6): 1H δ 3.86 (2H, dd, JHP = 10, JHH = 2,
1
3
N–CH2–P); 7.18 (1H, dt, JHP = 558, JHH = 2, P–H); 7.80–7.90
(4H, m, aryl H); 13C{1H} δ 38.0 (d, JCP = 98, N–CH2–P); 123.4,
1
131.5, 134.8 (aryl C); 167.3 (s, CvO); 31P δ 17.6 (dt, JPH = 558,
1
2JPH = 10). ESI-MS(−): m/z 223.5 [(M − H)−, calcd 224.1]. TLC
(EtOH : aq. NH4OH 1 : 1): Rf = 0.8. Elem. anal. (calcd for
C9H8NO4P, Mr = 225.1): C 48.0 (48.0); H 3.5 (3.2); N 6.2 (6.3).
mp 202 °C (with decomposition).
1-Hydroxy-ethane-1,1-bis[(aminomethyl)phosphinic acid]
(H2L1). Under an argon atmosphere, compound 2 (6.15 g,
27.3 mmol) was suspended in HMDS (100 mL) and the
mixture was heated at 110 °C under a gentle flow of argon over-
night. The mixture was cooled to RT and dry CH2Cl2 (200 mL)
was added. A solution of acetyl chloride (1.13 g; 14.4 mmol) in
dry CH2Cl2 (20 mL) was added dropwise and the mixture was
stirred at RT overnight. Then, the resulting solution was
dropped into EtOH (500 mL) and the resulting suspension was
Scheme 1 Structures of studied methylene-bis[(aminomethyl) phosphinic
acids] and other compounds discussed in the text.
on the central carbon atom (Scheme 1). The ligands can be
convenient in applications where rather strong acidity and
weak complexation ability of the phosphinic acid group is
desired.
Experimental
Materials and methods
Commercially available chemicals had synthetic purity and evaporated to dryness under reduced pressure. The solid was
were used as received. NMR spectra were recorded at 25 °C on dissolved in boiling water (50 mL) and treated with charcoal
a Varian NMR system operating at 300 MHz proton frequency while hot. The filtrate was cooled to RT and conc. aq. HCl
with an ASW probe. Chemical shifts were referenced to TMS (10 mL) was slowly added. The mixture was left to stand for 2 h
(δH = δC = 0 ppm) or tBuOH (δH = 1.25, δC = 31.2 ppm) and and the solid was collected on a medium-coarse glass frit,
H3PO4 (external standard, δP = 0 ppm) and are given in the washed with water and dried over P2O5 in vacuum. This crude
ppm scale and the coupling constants are given in Hz. ESI-MS intermediate 3 (5.5 g, obtained as a yellowish powder) was dis-
spectra were recorded on a Bruker Esquire 3000 spectrometer solved in 6 M aq. HCl (100 mL) and the solution refluxed for
with ESI ionization and ion-trap detection. High resolution MS 24 h. After cooling to RT, precipitated phthalic acid was filtered
spectra were measured on a Bruker APEX-Q FTMS. UV-Vis off. The filtrate was evaporated to dryness under reduced
spectra were measured on
a
Schimadzu UV-2401PC pressure and further co-evaporated three times with water
spectrometer at 25 °C in the wavelength range 200–800 nm. (50 mL). The crude product was purified on cation-exchange
TLC was performed with silica gel on aluminium sheets resin (Dowex 50, H+-form). Impurities were eluted off with
(Merck 10554 F254); the spots were detected with UV fluore- water and water : EtOH 1 : 1 mixtures. The pure product was
scence (λ = 254 nm) or visualized by iodine vapours.
eluted with 5% aq. ammonia. Fractions containing product
Phthalimido-methylphosphinic acid (2). Under an argon were treated with charcoal and the filtrate was evaporated to
atmosphere, dry (NH4)H2PO2 (20.0 g, 241 mmol) was sus- dryness. The residue was suspended in water (100 mL). The
pended in hexamethyldisilazane (HMDS, 100 mL) and the solid was collected on a glass frit, washed with EtOH and
mixture was heated at 110 °C under a gentle flow of argon over- dried over P2O5 in vacuum to give the product as a white
night. The mixture containing HP(OTMS)2 (1) was cooled to powder (1.74 g, 47%).
1
3
room temperature (RT) and dry CH2Cl2 (100 mL) was added.
3: NMR (5% Et3N in dmso-d6): H δ 1.35 (3H, t, JHP = 14,
The solution of (N-bromomethyl)phthalimide (15.0 g, CH3); 4.09 (4H, m, N–CH2–P); 7.75–7.90 (8H, m, aryl H);
62.5 mmol) in dry CH2Cl2 (300 mL) was added dropwise and 13C{1H} δ 18.3 (s, CH3); 37.0 (dd, 1JCP = 106; 3JCP = 9, N–CH2–P);
1
the mixture was stirred at RT overnight. Then, the resulting 70.8 (t, JCP = 97 Hz, P2C(CH3)–OH); 122.7, 132.0, 134.1
solution was dropped into EtOH (800 mL) and the solution (aryl C); 167.6 (s, CvO); 31P{1H} δ 28.8 (s). ESI-MS(−): m/z
was evaporated to dryness under reduced pressure. Crude 490.8 [(M − H)−, calcd 491.0]. TLC (MeCN : MeOH : aq. NH4OH
product was dissolved in boiling 1% aq. HCl (100 mL) and the 3 : 1 : 2): Rf = 0.4.
1
3
resulting suspension was filtered on a fine glass frit while hot.
The filtrate was cooled down and left standing overnight. The 14, CH3); 2.89 (4H, m, N–CH2–P); 13C{1H} δ 20.9 (s, CH3); 41.4
H2L1: NMR (NaOD/D2O, pD = 12): H δ 1.47 (3H, t, JHP
=
1
3
1
precipitate formed was collected on a glass frit and dissolved (dd, JCP = 98; JCP = 9, N–CH2–P); 77.0 (t, JCP = 86, P2C(CH3)–
in boiling water until a clear solution was formed. The solu- OH); 31P{1H} δ 36.8 (s). ESI-MS(−) m/z: 230.5 [(M − H)−, calcd
tion was cooled down and left overnight. The precipitate 231.0]; ESI-MS(+) m/z: 203.7 [(M + H − CH2NH2)+, calcd 204.1];
formed (containing mainly the disubstituted product) was 232.7 [(M + H+)+, calcd 233.05]; 254.7 [(M + Na)+, calcd 255.0];
filtered off on a glass frit and the filtrate was evaporated to 276.7 [(M + 2Na − H)+, calcd 277.0]. TLC (EtOH : aq. NH4OH
dryness. The solid residue was dissolved in a minimum 1 : 1): Rf = 0.4. Elem. anal. (calcd for C4H14N2O5P2·1.5H2O, Mr =
This journal is © The Royal Society of Chemistry 2013
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259.1): C 18.5 (18.4); H 6.6 (6.8); N 10.8 (10.5). mp 276 °C (with THF (50 mL) was slowly added to a cooled mixture (5 °C) of
decomposition). water (150 mL) and THF (50 mL). After stirring for 1 h, volatiles
(Hydroxy)(phenyl)methylene-bis[(aminomethyl)phosphinic were evaporated under reduced pressure. The resulting oil was
acid] (H2L2). Under an argon atmosphere, the compound 2 dissolved in a minimum amount of MeOH and an excess of
(5.00 g, 22.2 mmol) was suspended in HMDS (30 mL) and the Me2CO was added until two phases were formed. The upper
mixture was heated at 110 °C under a gentle flow of argon over- phase was discarded and the resulting oil was dried in vacuum
night. The mixture was cooled to RT and dry CHt2Cl2 (20 mL) for several days. The oil solidified to a colourless mass after
was added. The solution of benzoyl chloride (1.64 g, standing at 5 °C overnight (10.8 g, 82%).
1
2
11.7 mmol) in dry CH2Cl2 (20 mL) was added dropwise and
NMR (dmso-d6): H δ 2.40 (2H, t, JHP = 17, CH2); 7.10 (2H,
the mixture was stirred at RT overnight. Then, the reaction d, 1JHP = 561, P–H); 13C{1H} δ 33.4 (t, 1JCP = 80, CH2); 31P δ 19.3
mixture was dropped into EtOH (200 mL) and the resulting (dt, JPH = 561, JPH = 17). ESI-MS(−) m/z: 330.6 [(2M − 3H+ +
suspension was evaporated to dryness under reduced pressure. 2Na+)−, calcd 330.9]; ESI-MS(+) m/z: 332.8 [(2M − H+ + 2Na+)+,
The solid was dissolved in boiling H2O (50 mL) and treated calcd 332.9]. TLC (EtOH : NH4OH 1 : 1): Rf = 0.8. Elem. anal.
with charcoal while hot. The filtrate was then cooled to RT and (calcd for CH6O4P2·H2O, Mr = 162.0): C 7.6 (7.4); H 4.8 (5.0).
1
2
conc. aq. HCl was slowly added (5 mL). After 2 h, the suspen-
Methylene-bis[(aminomethyl)phosphinic acid] (H2L3). In a
sion was decanted off, the solid was dissolved in a mixture of 250 mL round-bottom flask, methylene-bis(phosphinic acid) 6
MeCN : CHCl3 : MeOH 1 : 1 : 1 (50 mL) and the resulting solu- (3.45 g; 21.3 mmol), dibenzylamine (5.00 mL; 95.5 mmol) and
tion was left standing overnight. The precipitate was collected paraformaldehyde (2.90 g; 96.6 mmol) were suspended in a
on a medium-coarse glass frit, washed several times with water mixture of 6 M aq. HCl (40 mL) and THF (40 mL) and stirred
and dried over P2O5 in vacuum. This crude intermediate 4 overnight at 50 °C. The reaction mixture was evaporated to
(3.93 g, obtained as a white powder) was dissolved in a mixture dryness and then co-evaporated three times with CH2Cl2, until
of 75% aq. N2H4 (80 mL) and EtOH (80 mL) and stirred at RT the residue solidified. The crude intermediate 7 (containing a
overnight. The mixture was evaporated to dryness and three large amount of dibenzylamine hydrochloride) was used for
times co-evaporated with EtOH. The residue was dissolved in a subsequent reaction without further purification. It was dis-
minimum amount of water and excess of EtOH was added. solved in MeOH (250 mL) under an argon atmosphere and
After standing overnight, the precipitate was collected on a ammonium formate (47.9 g; 760 mmol) and catalyst (10% w/t
medium-coarse glass frit. The solid was dissolved in water and Pd/C; 4.00 g) were added. The reaction mixture was refluxed
purified on anion-exchange resin (Dowex 1, OH−-form). Impu- for 2 h. Another portion of ammonium formate (28.7 g;
rities were eluted off with water, and the product was eluted 455 mmol) and catalyst (2.40 g) was added and the reaction
with 6 M aq. HCl. The fractions containing the product were mixture was refluxed for a further 3 h. After removal of volatiles
combined and evaporated to dryness. The solid was suspended under reduced pressure, the residue was co-evaporated several
in water (100 mL) and excess of EtOH was added. After stand- times with MeOH. The black residue was treated with water
ing overnight, the precipitate was collected on a medium- and the suspension was filtered off on a fine glass frit. The fil-
coarse glass frit, washed with EtOH and dried over P2O5 in trate was evaporated to dryness, the residue was dissolved in
vacuum to give the product as a white powder (1.63 g, 40%).
water and the amino acid was adsorbed on anion exchange
4: NMR (5% Et3N in dmso-d6): 1H δ 3.74 (4H, m, N–CH2–P); resin (Amberlite IRA 402, OH−-form). Impurities were eluted
7.10–7.20 (1H, m, aryl H); 7.20–7.30 (2H, m, aryl H); 7.82 (10H, off with water and the product was eluted with 6 M aq. HCl.
1
bs, aryl H); 13C{1H} δ 36.0 (d, JCP = 100 Hz, N–CH2–P); 77.2 (t, Fractions containing product were treated with charcoal, the
1JCP = 80 Hz, P2C(Ph)–OH); 122.8, 126.0, 126.2, 127.3, 131.7, filtrate was evaporated to dryness and the residue was co-evap-
134.3, 137.3 (aryl C); 167.6 (s, CvO); 31P{1H} δ 30.4 (s). TLC orated three times with water. The solid was dried in vacuum
(MeCN : MeOH : aq. NH4OH 3 : 1 : 2): Rf = 0.5. ESI-MS(−) m/z: over P2O5 to give the product as a white powder (3.84 g, 63%).
552.8 [(M − H+)−, calcd 553.1]; ESI-MS(+) m/z: 577.0 [(M +
7: NMR (CDCl3): H δ 1.99 (2H, t, JHP = 16, P–CH2–P); 3.03
1
2
Na+)+, calcd 577.1]; 656.1 [(M + NHEt3+)+, calcd 656.2].
(4H, d, JHP = 10, P–CH2–N); 4.35 (8H, m, CH2Ph); 7.35–7.45
2
1
H2L2: NMR (NaOD/D2O, pD = 6): H δ 3.11 (4H, m, N–CH2– (12H, m, aryl H); 7.50–7.60 (8H, m, aryl H); 13C{1H} δ 38.5 (t,
P); 7.35–7.50 (3H, m, aryl H); 7.70–7.80 (2H, m, aryl H); 1JCP = 81, P–CH2–P); 51.4 (d, JCP = 90, P–CH2–N); 58.1 (s,
1
1
1
13C{1H} δ 35.6 (d, JCP = 99, N–CH2–P); 81.7 (t, JCP = 96, P2C CH2Ph); 129.0, 129.5, 129.9, 131.0 (s, aryl C); 31P{1H} δ 17.4 (s).
(Ph)–OH); 126.5 (t, JCP = 4, arCH–arC–C–P2); 128.4 (s, aryl C); ESI-MS(−) m/z: 560.9 [(M − H+)−, calcd 561.2]; ESI-MS(+) m/z:
3
129.1 (s, aryl C); 137.4 (s, aryl C); 31P{1H} δ 28.3 (s). ESI-MS(−) 563.2 [(M + H+)+, calcd 563.2]; 585.2 [(M + Na+)+, calcd 585.2];
m/z: 292.5 [(M − H)−, calcd 293.1]; ESI-MS(+) m/z: 294.7 601.2 [(M + K+)+, calcd 601.2]. TLC (MeCN : CHCl3 : MeOH
[(M + H)+, calcd 295.1]; 316.8 [(M + Na)+, calcd 317.0]; 332.7 1 : 1 : 1): Rf = 0.5.
[(M + K)+, calcd 333.0]. TLC (EtOH : aq. NH4OH 1 : 1): Rf = 0.4.
H2L3: NMR (NaOD/D2O, pH = 7): H δ 2.47 (2H, t, JHP = 17,
1
2
Elem. anal. (calcd for C9H16N2O5P2·HCl·H2O, Mr = 348.7): C P–CH2–P); 3.18 (4H, d, JHP = 11, P–CH2–N); 13C{1H} δ 36.3 (t,
2
31.0 (31.0); H 5.5 (5.1); N 8.0 (7.8); Cl 11.2 (11.4). mp 225 °C 1JCP = 83, P–CH2–P); 39.5 (d, JCP = 99, P–CH2–N); 31P{1H} δ
1
(with decomposition).
18.5 (s). ESI-MS(−) m/z: 201.1 [(M − H+)−, calcd 201.0]; ESI-MS
Methylene-bis(phosphinic acid) (6). Under an argon atmos- (+) m/z: 203.3 [(M + H+)+, calcd 203.0]; 225.4 [(M + Na+)+, calcd
phere, a solution of CH2(PCl2)2 (5) (20.0 g; 91.8 mmol) in dry 225.0]; 241.4 [(M + K+)+, calcd 241.0]. TLC (EtOH : aq. NH4OH
2416 | Dalton Trans., 2013, 42, 2414–2422
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1 : 1): Rf = 0.7. Elem. anal. (C3H12N2O4P2·0.5HCl·H2O, Mr
=
Li2[Co4(H−1L1)3(OH)]·17.5H2O. Powdered
H2L1·1.5H2O
238.3): C 15.1 (14.8); H 6.1 (5.8); N 11.8 (11.5), Cl 7.4 (7.8). mp (26 mg, 0.1 mmol) was suspended in 0.1 M aq. CoCl2 (1 mL,
310 °C (with decomposition). 0.1 mmol). The 1 M aq. LiOH was added dropwise until all
Potentiometric titrations. Methodology of the potentio- material dissolved and the solution reached pH 8. Diffusion of
metric titrations and processing of the experimental data were ethanol vapour at RT yielded oil which slowly crystallized.
analogous to those previously reported.16 Titrations were Single crystals of Li2[Co4(H−1L1)3(OH)]·17.5H2O were obtained
carried out in a vessel thermostatted at 25 0.1 °C at ionic on standing for six weeks.
strength I = 0.1 M KNO3. The ligand-to-metal ratio was 1 : 1
(Hgua)4[Cu2(H−1L2)2]CO3·10H2O. Powdered H2L2·HCl·H2O
(and 2 : 1 in some cases) with cM = 0.004 M, the pH range was (35 mg, 0.1 mmol) was dissolved in 0.1 M aq. CuCl2 (1 mL,
1.7–12 (or till precipitation of metal hydroxide). Titrations were 0.1 mmol). The 1 M aq. (Hgua)2CO3 was added dropwise to
carried out at least three times, each consisting of about 40 reach pH 10. Diffusion of ethanol vapour at RT yielded single
points. The water ion product, pKw = 13.78, and stability con- crystals of [H2NvC(NH2)2]4[Cu2(H−1L2)2]CO3·10H2O on stand-
stants of M2+ − OH− systems were taken from ref. 17. The pro- ing for five days.
tonation constants βn calculated are concentration constants
and are defined by βn = [HnL]/([H]n × [L]) (log K1 = log β1; log Kn
X-ray diffraction study
= log βn − log βn−1). The stability constants are defined by βhlm
= [MmHhLl]/[M]m × [H]h × [L]l. The constants (with standard
The diffraction data were collected at 150 K (Cryostream
Cooler, Oxford Cryosystem) using a Nonius Kappa CCD diff-
deviations) were calculated with the program OPIUM.18
Throughout the paper, pH means −log [H+].
ractometer and Mo-Κα radiation (λ = 0.71073 Å) and analyzed
using the HKL DENZO program package.19 The structures were
solved by direct methods (SIR92),20 and refined by full-matrix
Preparation of single crystals
least-squares techniques (SHELXL97).21 All non-hydrogen
H2L1·0.5H2O. Powdered H2L1·1.5H2O (26 mg) was dissolved atoms were refined anisotropically. All hydrogen atoms were
in a mixture of 0.1 M aq. CuCl2 (1 mL) and 6 M aq. HCl located in the difference map of electron density; however,
(1 mL). Volatiles were removed under reduced pressure and they were placed in theoretical (C–H) or original (O–H) posi-
the oily residue was dissolved in water (1 mL). Single crystals tions with thermal parameters Ueq(H) = 1.2 Ueq(X) as their free
of H2L1·0.5H2O were formed on standing at RT for one week.
refinement led to some unrealistic bond lengths. Table 1 con-
H2L3·H2O. Powdered H2L3·0.5HCl·H2O (29 mg) was sus- tains selected crystallographic parameters for the structures
pended in 0.1 M aq. CoCl2 (1 mL). The 1 M aq. LiOH was reported in this paper. Data for the structures have been
added dropwise until all material dissolved and the solution deposited with the Cambridge Crystallographic Data Centre
reached pH 8. Diffusion of ethanol vapour at RT yielded oil with CCDC-898276 (H2L1·0.5H2O), 898277 (H2L3·H2O), 898278
which slowly crystallized. Single crystals of H2L3·H2O were (Li2[Co4(H−1L1)3 (OH)]·17.5H2O), and 898279 {(Hgua)4-
obtained on standing for three weeks.
[Cu2(H−1L2)2]CO3·10H2O} reference numbers.
Table 1 Experimental data of reported crystal structures
Parameter
H2L1·0.5H2O
H2L3·H2O
Li2[Co4(H−1L1)3(OH)]·17.5H2O
(Hgua)4[Cu2(H−1L2)2]CO3·10H2O
Formula
Mw
C4H15N2O5.5P2
241.12
C3H4N2O5P2
220.10
C12H69Co4Li2N6O33.5P6
1269.15
C23H70Cu2N16O23P4
1189.91
Colour
Shape
Colourless
Plate
Colourless
Prism
Red
Plate
Brownish green
Plate
Dimensions (mm)
0.10 × 0.31 × 0.45
Monoclinic
C2/c
16.4183(4)
6.7200(2)
17.8230(4)
—
101.253(1)
—
1928.62(9)
8
0.20 × 0.45 × 0.50
Orthorhombic
Pbcn
11.5649(4)
8.9009(3)
8.3936(3)
—
0.14 × 0.25 × 0.56
Orthorhombic
P212121
13.0426(3)
13.2471(4)
26.9972(7)
—
0.12 × 0.35 × 0.69
Triclinic
P1
Crystal system
Space group
a (Å)
b (Å)
c (Å)
14.1333(4)
14.2073(4)
14.4339(4)
69.875(1)
76.646(1)
65.391(1)
2461.05(12)
2
α (°)
β (°)
γ (°)
—
—
—
—
V (Å3)
Z
864.02(5)
4
1.692
0.493
464
4664.5(2)
4
1.807
1.706
2620
Dc (g cm−3
)
1.661
0.454
1016
1.606
1.086
1244
μ (mm−1
F (000)
)
Diffractions; observed (Io > 2σ(Io))
Parameters
2218; 2003
124
1.077
993; 944
56
1.127
10 660; 9956
622
1.038
22 429; 21 349
1226
1.027
G-o-f on F2
R; R′ (all data)
0.0261; 0.0302
0.0713; 0.0739
0.489; −0.262
0.0232; 0.0246
0.0690; 0.0702
0.325; −0.368
0.0293; 0.0331
0.0721; 0.0737
0.839; −0.517
0.0237; 0.0262
0.0604; 0.0618
0.428; −0.338
wR; wR′ (all data)
Difference max; min (e Å−3
)
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(dichlorophosphino)methane 5. The compound was hydro-
lyzed yielding methylene-bis(phosphinic acid) 6 (ref. 24)
that was consequently treated with paraformaldehyde and
Results and discussion
Synthesis
The studied compounds were synthesized using two different dibenzylamine. The three component Mannich-type
strategies (Scheme 2). Those containing a hydroxy group reaction yields protected bis(phosphinate) 7 in high yield.
attached to the bridging carbon atom were prepared from Pht- The target ligand H2L3 was obtained by hydrogenolysis of
protected (aminomethyl)phosphinate fragments. The reaction benzyl groups using Pd/C as the catalyst. This synthesis is
of bis(trimethylsilyloxy)phosphine 1 with (N-bromomethyl)- more straightforward than the amine alkylation approach
phthalimide followed by hydrolysis of the silylester groups used in synthesis of similar (aminomethyl)phosphinic-
gives a mixture of hypophosphorous acid, and monosubsti- phosphonic acid, NH2CH2–PO2H–CH2–PO3H2.25 Unlike
tuted and disubstituted products as previously reported.22 To geminal bis(H-phosphinates) slowly decomposing in aqueous
improve the procedure, we developed a simple and efficient solution,7 all the ligands are fully stable in aqueous solution at
method for separation of the mixture based on different solu- any pH.
bility of the components in water. In the next step, the
obtained phthalimido-methylphosphinic acid 2 is converted to
Acid–base and coordination properties in solution
the corresponding trimethylsilylphosphinate by reaction with
Solution behaviour of the title geminal bis(phosphinic acids)
hexamethyldisilazane and treated with acetyl- or benzoylchlor-
and their complexes was studied by potentiometry. The
ide. The reaction is analogous to that previously reported
for geminal bis(H-phosphinates)7,23 and for cyclic amino-bis-
studied bis[(aminomethyl)phosphinates] show similar proto-
(phosphinates)11 and proceeds in high yield. The target
nation constants (Table 2 and S1†). Phosphinic acid groups are
strongly acidic and their protonation takes place at pH < 3
(Fig. 1A). At weakly acidic and neutral regions, the only species
present in the solution is the neutral zwitterionic form, H2L,
ligands H2L1 and H2L2 were obtained after removal of the
phthalimide protecting groups by hydrochloric acid or by
hydrazine, respectively. Compound H2L3 was prepared using
where both protons are bound on amine nitrogen atoms. The
a “build up” strategy starting from commercially available bis
pKa values assigned to the amino groups are surprisingly high
if compared to those of simple (aminoalkyl)phosphinic acids
(Table 2). For the studied ligands, the values of the highest
constants are comparable to those of carboxylic and phospho-
nic amino acids. Also values of the second protonation con-
stants are noticeably high. The small differences between the
first and the second constants indicate independent protona-
tion of both distant amino groups. The high basicity of the
nitrogen atoms could be ascribed to the presence of intramole-
cular hydrogen bonds similar to those found in the solid state
(see below).
Stability constants of complexes of the title geminal bis
[(aminomethyl)phosphinates] with Cu2+, Zn2+, Ni2+ and Co2+
ions were determined from potentiometric titrations at 1 : 1
and 2 : 1 ligand-to-metal ratios. Despite excess of the ligand
used in the latter cases, no species of ML2 stoichiometry could
be identified. Experimentally determined stability constants of
the complexes are summarized in Table S2† and the derived
stability constants are given in Table 3. The distribution dia-
Scheme 2 Synthesis of studied geminal bis(phosphinates). (i) (N-Bromo-
grams are shown in Fig. 2, S1, S2 and S3.† Similarly to protona-
methyl)phthalimide in CH2Cl2, RT; (ii) 1. HMDS, 110 °C; 2. RCOCl in CH2Cl2, RT;
tion constants of the ligands, stability constants of their
3. EtOH; (iii) conc. aq. HCl, reflux or N2H4 in EtOH, RT; (iv) H2O in THF, RT; (v)
complexes, log KML, do not follow typical trends among amino
dibenzylamine, paraformaldehyde, aq. HCl in THF, 50 °C; (vi) NH4(HCOO), Pd/C
in MeOH, reflux.
acids. The presence of two highly basic nitrogen atoms and
Table 2 Protonation constants, log Ka, of the studied methylene-bis[(aminomethyl)phosphinic acids] (25 °C, I = 0.1 M) and related ligands
Constant
H2L1
H2L2
H2L3
AM2P16
Gly(P)26
Gly(PtBu 27
)
Gly26
H2pcpPh 15e
log Ka(L)
log Ka(HL)
log Ka(H2L)
10.00
8.89
1.35
9.84
8.55
<1
9.49
8.80
2.09
8.51
7.07
0.77
10.05
5.39
0.40
8.42
1.20
—
9.56
2.36
—
3.33a
1.35a
—
a I = 0.5 M NMe4Cl.
2418 | Dalton Trans., 2013, 42, 2414–2422
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Fig. 1 Distribution diagrams of H2L1 in the absence of metal ions (A) and in the presence of Cu2+ (B), Zn2+ (C) and Ni2+ (D) ions (cL = cM = 4 mM, I = 0.1 M, 25 °C).
of hydroxido complexes) and/or (ii) dissociation of a proton
from the hydroxo group attached to the central carbon atom
and the alcoholate coordination, as suggested in the case of
the H2L1 and H2L2 ligands. The sites of the deprotonations
cannot be distinguished by potentiometry; however, both
coordination modes might be present in the solutions (see
below).
Table 3 Equilibrium constants (log KML or pKa) in systems containing the title
ligands and some divalent metal ions
Ligand
Metal ion Equilibriuma
H2L1
H2L2
H2L3
Cu2+
Zn2+
Ni2+
Co2+
Cu2+ + (L)2− ⇌ [Cu(L)]
10.76 11.13
8.41 8.07
11.26 12.29 10.53
9.87
8.82
[Cu(L)] ⇌ [CuH−1(L)]− + H+
[CuH−1(L)] ⇌ [CuH−2(L)]2− + H+
Zn2+ + (L)2− ⇌ [Zn(L)]
Coordination modes in solution were studied more in
detail for the Cu2+ complexes. Presence of the hydroxyl group
in the molecule results in significantly different behaviour
among the Cu2+ complexes. Ligands H2L1 and H2L2 form dark
green water-soluble complexes at pH above 5. The electronic
spectra of the complexes (Fig. 2) were measured at pH corre-
sponding to the maximum abundance of [CuL] and [CuH−1L]
species in the distribution diagrams. The colour of the com-
plexes is mostly given by strong CT-bands, which are shifted to
the visible region with maxima around 310 and 360 nm for
CuL1 and CuL2, respectively. The shift of the CT-bands indi-
cates coordination of the alcoholate groups in the solution in
a similar manner as was found in the solid state (see below).
Analogous behaviour of dinuclear Cu2+ complexes was pre-
viously reported for various ligands.28 Similar spectra were
observed for both [CuL] and [CuH−1L] species. In the case of
the [CuL] complex, coordination of the alcoholate group indi-
cates protonation of one nitrogen atom. Thus, the ligand is
more likely coordinated in the tridentate manner by amine
nitrogen, phosphinate and alcoholate oxygen atoms. For the
case of coordination through the alcoholate oxygen atom, any
form of tetradentate binding is not possible for geometrical
6.78
8.04
6.51
8.77
6.29
8.58
—
7.51
8.41
—
[Zn(L)] ⇌ [ZnH−1(L)]− + H+
[ZnH−1(L)] ⇌ [ZnH−2(L)]2− + H+
Ni2+ + (L)2− ⇌ [Ni(L)]
10.72 11.02
7.87
9.04
7.13
8.57
[Ni(L)] ⇌ [NiH−1(L)]− + H+
[NiH−1(L)] ⇌ [NiH−2(L)]2− + H+
Co2+ + (L)2− ⇌ [Co(L)]
12.77 12.50
b
7.28
7.84
5.79
[Co(L)] ⇌ [CoH−1(L)]− + H+
[CoH−1(L)] ⇌ [CoH−2(L)]2− + H+
[CoH−2(L)] ⇌ [CoH−3(L)]3− + H+
b
b
b
b
8.18
8.01
11.69 10.03
a Proton dissociation sites are not distinguished (see text). b Not
determined due to the formation of precipitate.
two phosphinate groups result in higher stability constants of
the complexes when compared to those found for other amino-
alkylphosphonic/phosphinic acids (Table 4). Despite that,
determination of several stability constants was disabled by
formation of hydroxide precipitates in the alkaline region (pro-
nounced mainly in the case of the Co2+ ion). The complexes
with stoichiometry H−1ML, H−2ML and H−3ML are formed at
pH > 7; here, the negative stoichiometric coefficients represent
(i) dissociation of a coordinated water molecule (i.e. formation
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Fig. 3 Molecular structures of H2L1 (left) and H2L3 (right) found in the solid-
state structures of H2L1·0.5H2O and H2L3·H2O, showing medium–strong intra-
molecular hydrogen bonds.
Solid-state structure of the bis[(aminomethyl)phosphinic
acids] and their complexes
The structures of two ligands and two complexes in the solid
state were determined by X-ray diffraction. The ligands, H2L1
and H2L3, are practically insoluble in water and, therefore, the
single-crystals suitable for the analysis were isolated only from
mixtures containing metal ions. The presence of metal ions
increases solubility due to metal–ligand interaction and slows
down crystallization of the ligands. In both structures, the mol-
ecules are in the zwitterionic forms with protons localized on
nitrogen atoms. Presence of the substituents attached to the
central carbon atom of ligand H2L1 results in longer distances
from phosphorus to the central carbon and a smaller P–C–P
angle (Table S3†). Both structures are stabilized by hydrogen
bonds between the amine group and the oxygen atom of the
opposite phosphinate group (Fig. 3). The hydrogen bond
lengths are 2.67/2.80 Å and 2.76 Å for ligands H2L1 and H2L3,
respectively. These medium–strong hydrogen bonds are prob-
ably also present in solution and they could explain the high
values of amine protonation constants.
Fig. 2 UV-Vis spectra of Cu2+ complexes with the title bis[(aminomethyl)phos-
phinic acids] (25 °C, water).
Table 4 Comparison of stability constants, log KML, of complexes with the title
ligands and with the related amino acids
Metal
ion
H2L1 H2L2 H2L3 AM2P16 Gly(P)26 Gly(PtBu 27
)
Gly26
Cu2+
Zn2+
Ni2+
Co2+
10.76 11.13 9.87 7.64
8.12
5.00
5.25
4.52
5.37
—
3.62
3.17
8.12
4.96
5.78
4.67
Single-crystals of [H2NvC(NH2)]4[Cu2(H−1L2)2]CO3·10H2O
were obtained by slow diffusion of ethanol into the solution
containing ligand H2L2 and Cu2+ ions neutralized at pH 10
with guanidinium carbonate. An independent unit contains
two dinuclear complexes. Both independent complex units
possess the same coordination motif and their angles and dis-
tances differ only slightly (Fig. 4 and Table S4†). All Cu2+ ions
are coordinated in distorted octahedral geometry with two
amine nitrogen atoms and two alcoholate oxygen atoms orig-
inating from two different ligand molecules coordinated in the
equatorial plane. These two μ2-alcoholate oxygen atoms form
the bridge to the other Cu2+ ion which is also coordinated by
the remaining two amine groups. The Cu⋯Cu separations are
3.032 and 3.047 Å in the two independent units. Axial pos-
itions of the copper coordination polyhedrons are occupied by
phosphinate oxygen atoms. Due to Jahn–Teller distortion, the
coordination bonds to phosphinate oxygen atoms are signifi-
cantly longer (∼2.4–3.1 Å) compared to the distances between
the metal centre and the equatorial donor atoms (∼1.9–2.0 Å),
see Table S4.† The structure contains hydrate water molecules,
guanidinium and carbonate ions forming a rich system of
medium–strong hydrogen bonds.
6.78
7.87
6.51 6.29 4.12
7.13 7.51 5.58
7.28 5.79 4.07
—
reasons. In the case of the [MH−1L] complex, one could expect
similar dimeric species as was found in the solid state of the
CuL2 complex (see below). For both ligands L1 and L2 the
dinuclear complexes were also identified as major signals in
the high resolution MS spectra (Fig. S4†). Unfortunately, poten-
tiometry could not easily distinguish between monomeric and
oligomeric species.
In contrast, ligand H2L3 forms a light blue poorly soluble
Cu2+ complex and this system could be studied in solution
only due to slow kinetics of crystallization. The electronic
spectra (Fig. 2) show a weak d–d transition at around 680 nm
and a strong CT-band in the UV region (<300 nm) that could
be expected for amine and phosphinate coordination. Colour
and electronic spectra of the complex resemble those of the
bis(glycinato)copper complex.29 Thus, tetradentate coordi-
nation through both phosphinate oxygen atoms and both
amine groups could be expected.
2420 | Dalton Trans., 2013, 42, 2414–2422
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by an alcoholate donor (3.18–3.22 Å). The cubane-like core is
slightly distorted, with Co–O–Co and O–Co–O angles in the
ranges 94–99° and 81–85°, respectively. However, the geometry
of the cubane-like core is very similar to those found in analo-
gous structures bridged by polydentate ligands, like in citrato
or tris(carboxylato)methoxo complexes.30,31 The negative
charge of the whole cubane is compensated by two Li+ ions
chelated by uncoordinated phosphinate oxygen atoms of the
same ligand molecule. The coordination sphere of each Li+ ion
is completed by two water molecules. Selected relevant dis-
tances and angles are compiled in Tables S5 and S6.†
Fig. 4 One of the [Cu2(H−1L2)2]2− units found in the solid-state structure of
(Hgua)4[Cu2(H−1L2)2]CO3·10H2O. Hydrogen atoms attached to carbon atoms are
omitted for clarity reasons.
Conclusions
Three symmetrical methylene-bis[(aminomethyl)phosphinic
acids] bearing different substituents on the central carbon
atom, (NH2CH2)PO2H–C(R1)(R2)–PO2H(CH2NH2) where R1
OH, R2 = Me (H2L1), R1 = OH, R2 = Ph (H2L2) and R1,R2
=
=
H (H2L3), were synthesized. The compounds exhibit high basi-
cities of nitrogen atoms and high stabilities of the complexes
with divalent metal ions that are unusual for α-aminoalkylphos-
phinic acids. The solution and solid state studies of the com-
plexes have shown an important role of the hydroxo group
attached to the central carbon atom of the bis(phosphinate)
moiety that induces formation of dinuclear or polynuclear
complexes.
Acknowledgements
Support from the Grant Agency of the Czech Republic
(No. P207/10/P153), the Grant Agency of Charles University
(No. 310011) and from the Long-Term Research Plan of
the Ministry of Education of the Czech Republic (No.
MSM0021620857) is acknowledged. This work was carried out
in the framework of COST CM802 (PhoSciNet) Action.
We thank Dr Ivana Císařová (Charles University in Prague) for
performing X-ray measurements.
Fig. 5 Solid-state structure of the [Co4(OH)(H−1L1)3{Li(H2O)2}2] unit found in
the crystal structure of Li2[Co4(H−1L1)3(OH)]·17.5H2O. Hydrogen atoms attached
to carbon atoms are omitted for clarity reasons.
Slow diffusion of ethanol into the solution containing
ligand H2L1 and Co2+ ions (at pH 8) yielded single-crystals of
Li2[Co4(H−1L1)3(OH)]·17.5H2O. The core of the complex con-
sists of a cubane-like structure composed of four Co2+ ions
and four oxygen atoms forming μ3-bridges (Fig. 5). Three
oxygen atoms originate from the deprotonated hydroxo group
attached to the central carbon atoms of three ligand mole-
cules. The last oxygen atom belongs to a hydroxide anion.
Each of the bis(phosphinate) ligands is coordinated through
two phosphinate groups and one bridging alcoholate oxygen
atom to one Co2+ ion forming two five-membered chelate
rings. Such tridentate coordination disables coordination of
nitrogen atoms to the same metal ion and, thus, the
amine groups of each ligand are coordinated to two different
neighbouring Co2+ ions (those coordinated by the alcoholate
in μ3-bridging fashion). The coordination bonds, Co–O and
Co–N, are in the range expected for the Co2+ ion (∼2.1–2.2 Å).
The separation of Co⋯Co is in the range 3.13–3.22 Å, with
slightly closer separations of cobalt(II) ions bound through a
μ3-hydroxido bridge (3.13–3.16 Å) rather than those separated
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