Key words selectivity - substitution - phosphoryl chloride - phosphinate - phosphonate - Grignard
reagent - organozinc reagent
Organophosphinates 1 and organophosphonates 2 , the ester derivatives of organophosphinic 3 and organophosphonic acids, can be seen as intermediate compounds between the corresponding
phosphates and phosphine oxides. Hence, the chemical, physical, and biological properties
of phosphinates 1 and phosphonates 2 are in between these two extremes.[1 ] The synthesis of phosphinate 1 and phosphonate 2 derivatives is therefore an attractive approach to fine-tune the characteristics
of organophosphorus(V) compounds. The attractiveness of these two classes of molecules
is illustrated by their many applications. For example, they are used as halogen-free
flame retardants in plastics,[2 ] as extractants for liquid-liquid extraction in hydrometallurgy,[3 ] and solvometallurgy,[4 ] as grafting agents to modify metal oxide surfaces,[5 ] and as reagents for olefination reactions.[6 ] Moreover, phosphinates 1 and phosphonates 2 are important in the treatment of several diseases, typically as prodrugs for their
corresponding acid derivatives.[7 ] Noteworthy examples are nucleoside phosphonates applied in the treatment of various
DNA virus and retrovirus infections, such as hepatitis B and HIV.[8 ]
However, the utility of organophosphinates 1 is limited by their tedious multistep synthesis. The corresponding phosphinic acids
3 are the key intermediates in this synthesis and they form, after activation to phosphinic
halides, the desired phosphinates 1 via a nucleophilic substitution reaction (Scheme [1 ], path A).[9 ] Of course, first the organophosphinic acids 3 need to be prepared using, for example, a hydrophosphonation reaction of alkenes
with hypophosphorous acid 4 ,[10 ] a reaction between dialkyl hydrogen phosphites 5 and organometallic reagents followed by oxidation,[10 ] etc.[11 ]
[12 ] A generic strategy towards phosphinates 1 is not available yet.[10 ]
[13 ] The used synthetic pathway is therefore dependent on the structure of the desired
phosphinate 1 .
Scheme 1 Brief summary of the synthetic pathways towards organophosphinates 1 and organophosphonates 2
A more generic strategy is known for organophosphonates 2 . Phosphorus trichloride (6 ) can be substituted with an excess of alcohol in the presence of base and the resulting
phosphite ester 7 can be subjected to an Michaelis–Arbuzov reaction with a haloalkane to form a phosphonate
2 (Scheme [1 ], path B).[1 ]
[10 ]
[13 ] However, the latter reaction requires high temperatures and only primary haloalkanes
react readily. Under certain conditions, secondary haloalkanes might also react,
but tertiary haloalkanes and haloarenes are unreactive in the Michaelis–Arbuzov reaction.[14 ] Moreover, when the alkyl group of the alcohol and the haloalkane are different,
a mixture of phosphonates 2 might be formed. Besides this strategy, other less general synthetic pathways towards
phosphonates 2 have also been described.[1b ]
[11 ]
[15 ]
A more straightforward and general strategy to synthesize both phosphinates 1 and phosphonates 2 could be envisioned as the reaction between phosphoryl chloride (8 ) and, respectively, two or one equivalents of Grignard reagent, followed by quenching
with an excess of alcohol (Scheme [1 ], path C). This one-pot procedure would be shorter than the conventional synthetic
strategies, would use milder reaction conditions (i.e., heating is not required) and
would allow different substituents on the phosphorus (R1 ) and oxygen (R2 ) atoms. However, this one-pot protocol is currently not used for the synthesis of
either phosphinates 1 or phosphonates 2 . A poorly selective substitution of phosphoryl chloride (8 ) with Grignard reagents is often cited as the reason why this one-pot procedure is
unsuitable for the synthesis of phosphinates 1 and phosphonates 2 .[1a ]
[13 ] According to the literature, Grignard reagents have a tendency to completely substitute
phosphoryl chloride (8 ), but a detailed study of the extent of the side reactions has not been reported
yet.[13 ] It should also be noted that many examples that resulted in over-substitution used
an unfavorable addition order of the reagents, namely phosphoryl chloride (8 ) was added to the Grignard reagent. Adding the Grignard reagent to phosphoryl chloride
(8 ) can be expected to give better yields.[16 ] Moreover, reported examples of the reaction between phosphoryl chloride (8 ) and organometallic reagents were typically limited to aryl Grignard reagents,[16a ] whereas alkyl groups and other organometallic reagents have been much less studied.
Furthermore, most of these reports involved quenching the reaction with water, forming
a phosphinic or phosphonic acid. Preparing esters by quenching the reaction with
different alcohols is less common.
Given the current poor understanding of the extent of the selectivity for the substitution
reaction of phosphoryl chloride (8 ) with organometallic reagents, we set out to investigate this selectivity using NMR
spectroscopy and to examine the possibility of using this substitution reaction in
the synthesis of phosphinates 1 and phosphonates 2 . Based on the results, practical one-pot syntheses of phosphinates 1 and phosphonates 2 using commercially available starting materials were developed (Scheme [1 ], path C).
The first step of this work was to study the selectivity of the substitution reaction
of phosphoryl chloride (8 ) with one or two equivalents of Grignard reagent. In order to limit over-substitution,
the Grignard reagent was slowly added to an anhydrous diethyl ether solution of phosphoryl
chloride (8 ) while the solution was being cooled using an ice-salt mixture. Diethyl ether was
chosen as the reaction solvent because all the Grignard reagents used in this study
are commercially available as diethyl ether solutions. After addition of the Grignard
reagent, the reaction was stirred at room temperature to achieve complete conversion.
Samples were then taken and analyzed by 31 P NMR spectroscopy to estimate the relative amounts of the formed products. Preliminary
experiments with phenylmagnesium bromide showed that the formed phenylphosphonic dichloride
and diphenylphosphinic chloride were too poorly soluble in diethyl ether[16a ] to allow analysis of the reaction mixture by 31 P NMR spectroscopy. Because octylphosphonic dichloride and dioctylphosphinic chloride
are more soluble, the selectivity of the substitution reaction was determined by using
octylmagnesium bromide as the Grignard reagent.
Reacting one equivalent of octylmagnesium bromide with phosphoryl chloride (8 ) resulted in less than 10% of the desired octylphosphonic dichloride compound 9a (Table [1 ], entry 1). Instead, about half of the reaction mixture was doubly reacted dioctylphosphinic
chloride (10a ) and the other half unreacted phosphoryl chloride (8 ). Thus, the added octylmagnesium bromide reacted twice with phosphoryl chloride (8 ), which is in agreement with the reported tendency of Grignard reagents to completely
substitute phosphoryl chloride (8 ).[1a ]
[13 ] This lack of selectivity for monofunctionalization might be explained by considering
the magnesium salt that is formed as a side product during the reaction. This Lewis
acid will probably coordinate stronger to the more electron-rich octylphosphonic dichloride
(9a ) than to phosphoryl chloride (8 ), making the resulting octylphosphonic dichloride complex more electrophilic and
hence more reactive toward the Grignard reagent.
Table 1 Percentage of Phosphorus Compounds in the Reaction Mixture after P(O)Cl3 has Reacted with 1 or 2 Equiv of an Octylorganometallic Reagent
Entry
RMa
Composition of reaction mixture (%)b
P(O)Cl3
RP(O)Cl2
R2 P(O)Cl
R3 P(O)
1
RMgX (1 equiv)
43
9
43
1
2
R2 Cd (0.5 equiv)
43
48
–c
–c
3
R2 Zn (0.5 equiv)
22
73
–c
–c
4
RMgX (2 equiv)
–c
15
73
2
a R = n -C8 H17 .
b Percentage of phosphorus compounds in the reaction mixture as estimated by 31 P NMR analysis.
c Compound was not detected.
In contrast to using one equivalent, reacting two equivalents of octylmagnesium bromide
with phosphoryl chloride (8 ) did result in a selective reaction (Table [1 ], entry 4). Almost 75% of the reaction mixture consisted of the desired dioctylphosphinic
chloride (10a ), whereas only approximately 15% octylphosphonic dichloride (9a ) and a trace of trioctylphosphine oxide were formed. This shows that, contrary to
what is typically assumed in the literature, selective disubstitution of phosphoryl
chloride (8 ) with two equivalents of a Grignard reagent is possible. This selectivity might be
explained by considering the steric hindrance of the reaction between dioctylphosphinic
chloride (10a ) and the Grignard reagent. Hence, this side reaction with dioctylphosphinic chloride
(10a ) will be less favorable than the less sterically hindered reaction with octylphosphonic
dichloride (9a ).
Given that the above-mentioned reaction mixture consisted mostly of dioctylphosphinic
chloride, it should be possible to synthesize octyl dioctylphosphinate (1a ) by quenching the reaction with an excess of 1-octanol. After addition of 1-octanol
at a temperature below 0 °C, the reaction was stirred at room temperature until 31 P NMR analysis showed complete consumption of the dioctylphosphinic chloride intermediate.
It was found that pyridine needed to be added together with 1-octanol. In this way,
the formed side product HCl could be neutralized and complete conversion could be
achieved. This resulted in a reaction mixture that consisted mostly of the desired
octyl dioctylphosphinate (1a ) together with a small amount of dioctyl octylphosphonate (2a ). After extractive workup and purification by column chromatography, octyl dioctylphosphinate
(1a ) was isolated in a good yield of 63% (Scheme [2 ]).
Scheme 2 One-pot synthesis of phosphinates 1 using a selective disubstitution of P(O)Cl3 with 2 equiv of Grignard reagents
Similar results could be obtained with other alkyl groups (Scheme [2 ]). Reaction of phosphoryl chloride (8 ) with two equivalents of dodecylmagnesium bromide, followed by quenching with an
excess of 1-dodecanol provided dodecyl didodecylphosphinate (1b ) in an isolated yield of 55%. Furthermore, the more sterically hindered 2-ethylhexyl
bis(2-ethylhexyl)phosphinate (1c ) could be synthesized in a similar yield by starting from the correspondingly branched
Grignard reagent and alcohol. Besides alkyl Grignard reagents, phenylmagnesium bromide
also allowed selective disubstitution of phosphoryl chloride (8 ). However, phenol was not reactive enough to substitute the resulting diphenylphosphinic
chloride intermediate. Nonetheless, 1-octanol could react with diphenylphosphinic
chloride and octyl diphenylphosphinate (1d ) was isolated in a slightly lower yield than the other synthesized phosphinates 1 .
The last example illustrates another advantage of this one-pot procedure, namely that
the substituents on the phosphorus (R1 ) and oxygen (R2 ) atoms of the resulting phosphinate 1 do not need to be the same. Mixed phosphinates 1d –f can be easily made using the same procedure and in similar yields. For example, reaction
of phosphoryl chloride (8 ) with two equivalents of octylmagnesium bromide followed by quenching with an excess
of 2-ethylhexanol resulted in 2-ethylhexyl dioctylphosphinate (1e ) in a good yield of 58%. In a similar way, a phosphinic acid could be synthesized
if the dioctylphosphinic chloride intermediate was quenched with water. After extraction
and recrystallization, dioctylphosphinic acid (1f ) was isolated in an acceptable yield.
This one-pot procedure is, compared to the different traditional multistep synthesis
routes of phosphinates 1 , much more straightforward and general. Moreover, the overall yield of this process
is, due to its shorter synthetic pathway, as good as or even better than those obtained
via the traditional synthesis routes (Scheme [1 ], path A).[9 ]
[10 ]
[11 ]
[13 ]
Given the success of disubstitution of phosphoryl chloride (8 ), selective monofunctionalization was further investigated using organometallic reagents
other than Grignard reagents. Similar to phosphoryl chloride (8 ), reaction of phosphorus trichloride (6 ) with Grignard reagents is known to result in over-substitution.[1a ]
[17 ] However, is has been reported that reaction of phosphorus trichloride (6 ) with milder alkylating reagents, such as organomercury,[18 ] organolead[19 ] and organocadmium[20 ] reagents, did allow selective monoalkylation. Therefore, it was tested whether
an organocadmium reagent could result in a similar selective monofunctionalization
reaction with phosphoryl chloride (8 ). Organomercury and organolead compounds were not investigated due to their very
high toxicity.[21 ] It should be mentioned that also organocadmium compounds are toxic; however, they
are less toxic than organomercury compounds and they are more commonly used as reagents
in organic synthesis than organolead compounds.[22 ]
Dioctylcadmium was synthesized in situ by the reaction of octylmagnesium bromide with
anhydrous CdCl2 in diethyl ether at room temperature. After addition of one equivalent (relative
to the initial amount of octylmagnesium bromide) of phosphoryl chloride (8 ) at a temperature below 0 °C, the reaction mixture was stirred at room temperature.
Unfortunately, no reaction was observed at this temperature. Nevertheless, a slow
reaction did occur when the reaction mixture was heated at reflux. Over-substitution
to dioctylphosphinic chloride (10a ) was not detected and the major product was the desired octylphosphonic dichloride
(9a ) (Table [1 ], entry 2). Hence, with this less strongly alkylating organocadmium reagent, selective
monofunctionalization of phosphoryl chloride (8 ) was indeed possible. After 45 hours, almost half of the reaction mixture consisted
of the monoalkylated product, the rest was mostly unreacted phosphoryl chloride (8 ).
As dioctylcadmium was not reactive enough to allow complete conversion, even after
45 hours of reflux, dioctylzinc was used as a more reactive and less toxic alternative.
Dioctylzinc was synthesized and used in a similar manner as dioctylcadmium. However,
due to its higher reactivity, dioctylzinc did react with phosphoryl chloride (8 ) at room temperature. After 20 hours, almost 75% of the reaction mixture consisted
of the desired octylphosphonic dichloride (9a ) (Table [1 ], entry 3). Dioctylzinc reacted, just like dioctylcadmium, selectively with phosphoryl
chloride (8 ) and over-substitution to dioctylphosphinic chloride (10a ) was not detected. The amount of monooctyl product in the reaction mixture after
reaction with 0.5 equivalent of dioctylzinc (Table [1 ], entry 3) was similar to the amount of dioctyl product after reaction with 2 equivalents
of Grignard reagent (Table [1 ], entry 4). Therefore, it is possible to tune the selectivity of the substitution
reaction of phosphoryl chloride (8 ) by choosing a proper organometallic reagent.
Selective monoalkylation of phosphoryl chloride (8 ) to octylphosphonic dichloride was used next to develop a one-pot procedure for the
synthesis of the corresponding phosphonate 2a . Hence, the reaction of dioctylzinc with phosphoryl chloride (8 ) was quenched with an excess of 1-octanol in the presence of pyridine. The reaction
mixture was cooled below 0 °C during the addition of these two reagents and was afterwards
stirred at room temperature until 31 P NMR analysis showed complete consumption of the octylphosphonic dichloride intermediate.
The resulting mixture consisted mostly of dioctyl octylphosphonate (2a ) together with a smaller amount of trioctyl phosphate. This trioctyl phosphate was
formed from the reaction between 1-octanol and the remaining phosphoryl chloride (8 ). Unfortunately, the desired dioctyl octylphosphonate (2a ) was found to be less stable than the corresponding phosphinate 1a . Therefore, more product was lost during purification and dioctyl octylphosphonate
(2a ) was isolated in a lower yield of 46% (Scheme [3 ]).
Scheme 3 One-pot synthesis of phosphonates 2 using a selective monosubstitution of P(O)Cl3 with 0.5 equiv of organozinc reagents (pyridine was not added in the case of phosphonic
acid 2f )
The scope of the one-pot synthesis of phosphonates 2 (Scheme [3 ]) is the same as the scope of the one-pot synthesis of phosphinates 1 (Scheme [2 ]). Unfortunately, all the synthesized phosphonates 2 were less stable than their phosphinate analogues 1 and were isolated in a lower yield. Nonetheless, phosphonates 2 with other alkyl groups, such as dodecyl (in compound 2b ) and the branched 2-ethylhexyl (in compounds 2c and 2e ) could be synthesized in moderate yields. In contrast, reaction of phosphoryl chloride
(8 ) with diphenylzinc followed by quenching with an excess of 1-octanol gave the corresponding
dioctyl phenylphosphonate (2d ) in a low yield. The major product was actually trioctyl phosphate and a significant
amount of octyl diphenylphosphinate (1d ) was also present, indicating that 0.5 equivalent of diphenylzinc did not react selectively
with phosphoryl chloride (8 ).
Mixed phosphonates, with different substituents on the phosphorus (R1 ) and oxygen (R2 ) atoms, can be easily prepared using this one-pot procedure. For example, bis(2-ethylhexyl)
octylphosphonate (2e ) was obtained in a similar yield as its trioctyl derivative 2a by reacting dioctylzinc with phosphoryl chloride (8 ) followed by quenching with an excess of 2-ethylhexanol. Moreover, octylphosphonic
acid (2f ) can be synthesized by quenching the reaction of dioctylzinc with water. Anhydride
formation limited the yield of the desired acid 2f but this can be reduced by not adding pyridine to the reaction mixture. In this way,
octylphosphonic acid (2f ) was isolated in a moderate yield.
The yields of the one-pot synthesis of phosphonates 2 are in general lower than those obtained for the traditional synthesis of phosphonates
2 based on the Michaelis–Arbuzov reaction (Scheme [1 ], path B).[1 ]
[10 ]
[13 ] Nevertheless, this new procedure is a viable alternative for those cases where the
Michaelis–Arbuzov reaction does not work.[14 ] Moreover, this one-pot synthesis requires only one purification step, compared to
the two purification steps required in the traditional strategy, uses milder reaction
conditions than the Michaelis–Arbuzov reaction and is well suited for the synthesis
of mixed phosphonates.
In conclusion, the selectivity of the substitution reaction of phosphoryl chloride
(8 ) with organometallic reagents was investigated using NMR spectroscopy. It was found
that 2 equivalents of octylmagnesium bromide reacted selectively to dioctylphosphinic
chloride and that 0.5 equivalent of dioctylzinc reacted selectively to octylphosphonic
dichloride. Hence, it is possible to tune the selectivity of the substitution reaction
of phosphoryl chloride (8 ) by choosing a proper organometallic reagent. These results were used to develop
one-pot synthetic methods for the preparation of phosphinates 1 and phosphonates 2 using commercially available Grignard reagents and alcohols. In this way, phosphinates
1 were synthesized in good yields and phosphonates 2 , due to their lower stability, in moderate yields. Both procedures allow the synthesis
of compounds with different substituents, of mixed systems and of their phosphinic
and phosphonic acid derivatives. Compared to the traditional strategies to synthesize
phosphinates 1 and phosphonates 2 , these one-pot procedures are shorter, more straightforward and more general.
All reactions were carried out in oven-dried glassware under a N2 atmosphere. POCl3 (99%), octylmagnesium bromide (2.0 M in Et2 O), (2-ethylhexyl)magnesium bromide (1.0 M in Et2 O), anhyd CdCl2 (99%), 1-octanol (99%), and 1-dodecanol (98%) were purchased from Acros Organics.
Dodecylmagnesium bromide (1.0 M in Et2 O) and phenylmagnesium bromide (3.0 M in Et2 O) were purchased from Sigma-Aldrich. 2-Ethyl-1-hexanol (99%) was purchased from Alfa
Aesar, pyridine (99.7%) was purchased from VWR and anhyd ZnCl2 (98–100%) was purchased from Chem-Lab. Anhyd Et2 O was obtained using a MBRAUN SPS-800 system. For column chromatography, 0.060–0.200
mm (60 A) silica gel from Acros Organics was used as the stationary phase. All chemicals
were used as received without further purification.
1 H and 13 C NMR spectra were recorded at r.t. in CDCl3 on a Bruker Ascend 400 MHz instrument operating at a frequency of 400 MHz for 1 H, 100 MHz for 13 C and 162 MHz for 31 P. 1 H chemical shifts were referenced to TMS (0.00 ppm), 13 C chemical shifts were referenced to the CDCl3 solvent signal (77.16 ppm) and 31 P chemical shifts were referenced to aq 85% H3 PO4 (0.00 ppm). Melting points were determined on a Mettler-Toledo DSC882e instrument
under a He atmosphere using a heating rate of 5 °C min–1 . IR spectra were recorded on a Bruker Vertex 70 ATR-FTIR spectrophotometer. Low-resolution
mass spectra were recorded on a Thermo Finnigan LCQ Advantage instrument (ESI mode).
CHN elemental analysis was performed on a Thermo Scientific Flash 2000 Organic Elemental
Analyzer.
Phosphinates 1; General Procedure
Phosphinates 1; General Procedure
To an oven-dried 100 mL two-necked flask, fitted with a reflux condenser were added
anhyd Et2 O (amount depending on the concentration of the used Grignard reagent solution) and
POCl3 (0.93 mL, 10 mmol, 1 equiv). The solution was cooled in an ice-salt mixture and a
Grignard reagent (20 mmol, 2 equiv) solution in Et2 O was slowly added. After stirring with cooling for 30 min, the reaction mixture was
brought to r.t. and stirred for the indicated time. The mixture was then cooled again
in an ice-salt mixture and the alcohol (20 mmol, 2 equiv) and pyridine (1.8 mL, 22
mmol, 2.2 equiv) were slowly added. Stirring with cooling for 5 min was followed by
reaction at r.t. The reaction was quenched after the indicated time by cooling in
an ice-salt mixture and adding sat. aq NH4 Cl (5 mL). The crude mixture was then poured into CH2 Cl2 (100 mL), washed three times with dil HCl (1–2%, 100 mL in total), dried (MgSO4 ), filtered, and evaporated to dryness. The excess of alcohol was removed using a
short-path vacuum distillation apparatus and the resulting crude product was purified
by column chromatography.
Octyl Dioctylphosphinate (1a)
Octyl Dioctylphosphinate (1a)
[CAS Reg. No. 7065-29-4]
Prepared according to the general phosphinate synthesis procedure using anhyd Et2 O (20 mL), octylmagnesium bromide (10 mL, 20 mmol, 2 equiv), and 1-octanol (3.2 mL,
20 mmol, 2 equiv). The reaction with the Grignard reagent was stirred at r.t. for
5 h and the reaction with the alcohol was stirred at r.t. for 21 h. After extractive
workup, the excess of 1-octanol was removed using a short-path vacuum distillation
apparatus at 250 °C. The resulting crude product was purified by column chromatography
(silica gel; CH2 Cl2 /EtOAc; 8:2 v/v), providing the pure compound as a slightly yellowish liquid; yield:
2.52 g (63%).
IR (ATR): 2923, 2854, 1465, 1207, 1018, 721 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 3.95 (q, J = 6.6 Hz, 2 H), 1.72–1.64 (m, 6 H), 1.61–1.52 (m, 4 H), 1.41–1.22 (m, 30 H), 0.88
(t, J = 6.3 Hz, 9 H).
13 C NMR (CDCl3 , 100 MHz): δ = 64.1, 64.1, 32.0, 31.2, 31.0, 30.9, 29.4, 29.3, 29.3, 29.2, 28.6,
27.7, 25.8, 22.8, 22.1, 22.1, 14.2.
31 P NMR (CDCl3 , 162 MHz): δ = 57.8.
MS (ESI): m /z = 403 [M + H]+ , 425 [M + Na]+ , 805 [2 M + H]+ , 827 [2 M + Na]+ .
Anal. Calcd for C24 H51 O2 P: C, 71.59; H, 12.77. Found: C, 71.40; H, 12.66.
Dodecyl Didodecylphosphinate (1b)
Dodecyl Didodecylphosphinate (1b)
Prepared according to the general phosphinate synthesis procedure using anhyd Et2 O (10 mL), dodecylmagnesium bromide (20 mL, 20 mmol, 2 equiv), and 1-dodecanol (4.5
mL, 20 mmol, 2 equiv). The reaction with the Grignard reagent was stirred at r.t.
for 24 h and the reaction with the alcohol was stirred at r.t. for 24 h. After extractive
workup, the excess of 1-dodecanol was removed using a short-path vacuum distillation
apparatus at 300 °C. The resulting crude product was purified by column chromatography
(silica gel; CH2 Cl2 /EtOAc; 9:1 v/v), providing the pure compound as a white solid; yield: 3.16 g (55%);
mp 39–41 °C.
IR (ATR): 2916, 2848, 1463, 1184, 966, 773 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 3.95 (q, J = 6.6 Hz, 2 H), 1.75–1.61 (m, 6 H), 1.61–1.50 (m, 4 H), 1.40–1.22 (m, 54 H), 0.88
(t, J = 6.6 Hz, 9 H).
13 C NMR (CDCl3 , 100 MHz): δ = 64.1, 64.1, 32.1, 31.1, 31.0, 30.9, 29.8, 29.7, 29.7, 29.5, 29.5,
29.4, 29.3, 28.6, 27.7, 25.8, 22.8, 22.1, 22.1, 14.3.
31 P NMR (CDCl3 , 162 MHz): δ = 57.8.
MS (ESI): m /z = 571 [M + H]+ , 593 [M + Na]+ , 1142 [2 M + H]+ , 1164 [2 M + Na]+ , 1734 [3 M + Na].
Anal. Calcd for C36 H75 O2 P: C, 75.73; H, 13.24. Found: C, 76.43; H, 13.17.
2-Ethylhexyl Bis(2-ethylhexyl)phosphinate (1c)
2-Ethylhexyl Bis(2-ethylhexyl)phosphinate (1c)
[CAS Reg. No. 36333-32-1]
Prepared according to the general phosphinate synthesis procedure using anhyd Et2 O (10 mL), (2-ethylhexyl)magnesium bromide (20 mL, 20 mmol, 2 equiv), and 2-ethyl-1-hexanol
(3.1 mL, 20 mmol, 2 equiv). The reaction with the Grignard reagent was stirred at
r.t. for 18.5 h and the reaction with the alcohol was stirred at r.t. for 3 days.
After extractive workup, the excess of 2-ethyl-1-hexanol was removed using a short-path
vacuum distillation apparatus at 150 °C. The resulting crude product was purified
by column chromatography (silica gel; CH2 Cl2 /EtOAc; 95:5 v/v), providing the pure compound as a colorless liquid; yield: 2.08
g (52%).
IR (ATR): 2957, 2927, 1460, 1224, 1017, 820 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 3.92–3.79 (m, 2 H), 1.81–1.71 (m, 2 H), 1.66–1.60 (m, 4 H), 1.58–1.34
(m, 11 H), 1.34–1.16 (m, 14 H), 1.07–0.69 (m, 18 H).
13 C NMR (CDCl3 , 100 MHz): δ = 66.0, 40.6, 40.5, 34.0, 33.9, 33.7, 32.8, 30.2, 29.1, 28.8, 28.7,
27.2, 27.1, 27.0, 23.6, 23.2, 23.1, 14.3, 14.2, 11.1, 10.5, 10.5.
31 P NMR (CDCl3 , 162 MHz): δ = 57.6 (t, J = 9.9 Hz).
MS (ESI): m /z = 403 [M + H]+ , 425 [M + Na]+ , 805 [2 M + H]+ , 827 [2 M + Na]+ .
Anal. Calcd for C24 H51 O2 P: C, 71.59; H, 12.77. Found: C, 71.81; H, 12.62.
Octyl Diphenylphosphinate (1d)
Octyl Diphenylphosphinate (1d)
[CAS Reg. No. 3389-73-9]
Prepared according to the general phosphinate synthesis procedure using anhyd Et2 O (40 mL), phenylmagnesium bromide (6.7 mL, 20 mmol, 2 equiv), and 1-octanol (3.2
mL, 20 mmol, 2 equiv). The reaction with the Grignard reagent was stirred at r.t.
for 21.5 h and the reaction with the alcohol was stirred at r.t. for 25.5 h. After
extractive workup, the excess of 1-octanol was removed using a short-path vacuum distillation
apparatus at 250 °C. The resulting crude product was purified by column chromatography
(silica gel; CH2 Cl2 /EtOAc; 9:1 v/v), providing the pure compound as a slightly yellowish liquid; yield:
1.45 g (44%).
IR (ATR): 2925, 1438, 1227, 1129, 991, 727, 694, 560, 537 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.81 (ddd, J = 12.2, 8.2, 1.3 Hz, 4 H), 7.56–7.48 (m, 2 H), 7.49–7.40 (m, 4 H), 4.02 (q, J = 6.7 Hz, 2 H), 1.76–1.68 (m, 2 H), 1.43–1.34 (m, 2 H), 1.33–1.22 (m, 8 H), 0.87
(t, J = 6.9 Hz, 3 H).
13 C NMR (CDCl3 , 100 MHz): δ = 132.6, 132.2, 132.2, 131.9, 131.8, 131.2, 128.7, 128.6, 65.2, 65.2,
31.9, 30.7, 30.7, 29.3, 29.3, 25.8, 22.8, 14.2.
31 P NMR (CDCl3 , 162 MHz): δ = 31.3.
MS (ESI): m /z = 331 [M + H]+ , 353 [M + Na]+ , 661 [2 M + H]+ , 683 [2 M + Na]+ .
Anal. Calcd for C20 H27 O2 P: C, 72.70; H, 8.24. Found: C, 73.23; H, 8.36.
2-Ethylhexyl Dioctylphosphinate (1e)
2-Ethylhexyl Dioctylphosphinate (1e)
[CAS Reg. No. 1400694-65-6]
Prepared according to the general phosphinate synthesis procedure using anhyd Et2 O (20 mL), octylmagnesium bromide (10 mL, 20 mmol, 2 equiv), and 2-ethyl-1-hexanol
(3.1 mL, 20 mmol, 2 equiv). The reaction with the Grignard reagent was stirred at
r.t. for 20 h and the reaction with the alcohol was stirred at r.t. for 24 h. After
extractive workup, the excess of 2-ethyl-1-hexanol was removed using a short-path
vacuum distillation apparatus at 150 °C. The resulting crude product was purified
by column chromatography (silica gel; CH2 Cl2 /EtOAc; 8:2 v/v), providing the pure compound as a slightly yellowish liquid; yield:
2.35 g (58%).
IR (ATR): 2924, 2855, 1461, 1208, 1016, 811 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 3.90–3.81 (m, 2 H), 1.75–1.62 (m, 4 H), 1.61–1.50 (m, 5 H), 1.42–1.34
(m, 6 H), 1.33–1.22 (m, 22 H), 0.96–0.83 (m, 12 H).
13 C NMR (CDCl3 , 100 MHz): δ = 66.2, 66.1, 40.5, 40.5, 31.9, 31.1, 31.0, 30.2, 29.2, 29.2, 29.1,
28.5, 27.6, 23.6, 23.1, 22.8, 22.2, 22.1, 14.2, 14.2, 11.1.
31 P NMR (CDCl3 , 162 MHz): δ = 57.6.
MS (ESI): m /z = 403 [M + H]+ , 425 [M + Na]+ , 805 [2 M + H]+ , 827 [2 M + Na]+ .
Anal. Calcd for C24 H51 O2 P: C, 71.59; H, 12.77. Found: C, 72.18; H, 12.78.
Dioctylphosphinic Acid (1f)
Dioctylphosphinic Acid (1f)
[CAS Reg. No. 683-19-2]
To an oven-dried 100 mL two-neck flask, fitted with a reflux condenser were added
anhyd Et2 O (20 mL) and POCl3 (0.93 mL, 10 mmol, 1 equiv). The solution was cooled in an ice-salt mixture and octylmagnesium
bromide (10 mL, 20 mmol, 2 equiv) was slowly added. After stirring with cooling for
30 min, the reaction mixture was brought to r.t. and stirred for 19.5 h. The mixture
was then cooled again in an ice-salt mixture, and H2 O (5 mL) and pyridine (1.8 mL, 22 mmol, 2.2 equiv) were slowly added. Stirring with
cooling for 5 min was followed by reaction at r.t. for 7 h. The crude mixture was
then poured into CH2 Cl2 (100 mL), washed three times with dil HCl (1–2%, 100 mL in total), dried (MgSO4 ), filtered, and evaporated to dryness. The resulting crude product was purified by
recrystallization from hot heptane (50 mL), filtered, and washed with pentane, providing
the pure compound as a white solid; yield: 1.52 g (52%); mp 83–84 °C.
IR (ATR): 2915, 2846, 1463, 967, 779 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 10.52 (s, 1 H), 1.71–1.52 (m, 8 H), 1.43–1.33 (m, 4 H), 1.33–1.20
(m, 16 H), 0.87 (t, J = 6.8 Hz, 6 H).
13 C NMR (CDCl3 , 100 MHz): δ = 32.0, 31.1, 31.0, 29.6, 29.3, 29.3, 28.7, 22.8, 21.7, 21.7, 14.2.
31 P NMR (CDCl3 , 162 MHz): δ = 60.4.
MS (ESI): m /z = 289 [M – H]– , 579 [2 M – H]– , 601 [2 M – 2 H + Na]– .
Anal. Calcd for C16 H35 O2 P: C, 66.17; H, 12.15. Found: C, 66.67; H, 12.07.
Phosphonates 2; General Procedure
Phosphonates 2; General Procedure
To an oven-dried 100 mL two-necked flask, fitted with a reflux condenser were added
anhyd ZnCl2 (0.75 g, 5.5 mmol, 0.55 equiv) and anhyd Et2 O (amount depending on the concentration of the used Grignard reagent solution).
The mixture was cooled in an ice-bath and a Grignard reagent (10 mmol, 1 equiv) solution
in Et2 O was slowly added. The reaction mixture was stirred 10 more min at 0 °C followed
by stirring at r.t. for the indicated time. The solution was then cooled in an ice-salt
mixture and POCl3 (0.93 mL, 10 mmol, 1 equiv) was added. After stirring with cooling for 5 min, the
mixture was brought to r.t. and stirred for the indicated time. The mixture was cooled
again in an ice-salt mixture and the alcohol (30 mmol, 3 equiv) and pyridine (2.7
mL, 33 mmol, 3.3 equiv) were slowly added. Stirring with cooling for 5 min was followed
by reaction at r.t. The reaction was quenched after the indicated time by cooling
in an ice-salt mixture and adding dil HCl (1–2%, 5 mL). The crude mixture was then
poured into CH2 Cl2 (100 mL), washed three times with dil HCl (1–2%, 100 mL in total), dried (MgSO4 ), filtered, and evaporated to dryness. The excess of alcohol was removed using a
short-path vacuum distillation apparatus and the resulting crude product was purified
by column chromatography.
Dioctyl Octylphosphonate (2a)
Dioctyl Octylphosphonate (2a)
[CAS Reg. No. 7098-33-1]
Prepared according to the general phosphonate synthesis procedure using anhyd Et2 O (20 mL), octylmagnesium bromide (5 mL, 10 mmol, 1 equiv), and 1-octanol (4.7 mL,
30 mmol, 3 equiv). The corresponding organozinc reagent was synthesized by stirring
2 h at r.t. The reaction with the formed organozinc reagent was stirred at r.t. for
51 h and the reaction with the alcohol was stirred at r.t. for 17 h. After extractive
workup, the excess of 1-octanol was removed using a short-path vacuum distillation
apparatus at 200 °C. The resulting crude product was purified by column chromatography
(silica gel; CH2 Cl2 / EtOAc; 95:5 v/v), providing the pure compound as a slightly yellowish liquid; yield:
1.92 g (46%).
IR (ATR): 2923, 2854, 1465, 1248, 996, 722 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 4.06–3.94 (m, 4 H), 1.77–1.53 (m, 10 H), 1.39–1.25 (m, 28 H), 0.88
(t, J = 6.4 Hz, 9 H).
13 C NMR (CDCl3 , 100 MHz): δ = 65.7, 65.6, 32.0, 31.9, 30.9, 30.8, 30.7, 30.7, 29.4, 29.3, 29.2,
26.4, 25.7, 25.0, 22.8, 22.6, 22.6, 14.2.
31 P NMR (CDCl3 , 162 MHz): δ = 32.8.
MS (ESI): m /z = 419 [M + H]+ , 441 [M + Na]+ , 837 [2 M + H]+ , 859 [2 M + Na]+ .
Anal. Calcd for C24 H51 O3 P: C, 68.86; H, 12.28. Found: C, 69.31; H, 12.24.
Didodecyl Dodecylphosphonate (2b)
Didodecyl Dodecylphosphonate (2b)
Prepared according to the general phosphonate synthesis procedure using anhyd Et2 O (15 mL), dodecylmagnesium bromide (10 mL, 10 mmol, 1 equiv), and 1-dodecanol (6.7
mL, 30 mmol, 3 equiv). The corresponding organozinc reagent was synthesized by stirring
3 h at r.t. The reaction with the formed organozinc reagent was stirred at r.t. for
46 h and the reaction with the alcohol was stirred at r.t. for 5 h. After extractive
workup, the excess of 1-dodecanol was removed using a short-path vacuum distillation
apparatus at 300 °C. The resulting crude product was purified by column chromatography
(silica gel; CH2 Cl2 /EtOAc; 95:5 v/v), providing the pure compound as a white solid; yield: 2.12 g (36%);
mp 34–36 °C.
IR (ATR): 2913, 2847, 1469, 1233, 992, 837, 718 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 4.08–3.91 (m, 4 H), 1.76–1.68 (m, 2 H), 1.67–1.62 (m, 4 H), 1.62–1.55
(m, 2 H), 1.42–1.16 (m, 54 H), 0.88 (t, J = 6.8 Hz, 9 H).
13 C NMR (CDCl3 , 150 MHz): δ = 65.6, 65.6, 32.1, 30.8, 30.8, 30.7, 30.7, 29.8, 29.8, 29.8, 29.7,
29.7, 29.6, 29.5, 29.4, 29.3, 26.2, 25.7, 25.2, 22.8, 22.6, 22.6, 14.3.
31 P NMR (CDCl3 , 162 MHz): δ = 32.8.
MS (ESI): m /z = 558 [M + H]+ , 610 [M + Na]+ .
Anal. Calcd for C36 H75 O3 P: C, 73.67; H, 12.88. Found: C, 74.30; H, 12.82.
Bis(2-ethylhexyl) (2-Ethylhexyl)phosphonate (2c)
Bis(2-ethylhexyl) (2-Ethylhexyl)phosphonate (2c)
[CAS Reg. No. 126-63-6]
Prepared according to the general phosphonate synthesis procedure using anhyd Et2 O (15 mL), (2-ethylhexyl)magnesium bromide (10 mL, 10 mmol, 1 equiv), and 2-ethyl-1-hexanol
(4.7 mL, 30 mmol, 3 equiv). The corresponding organozinc reagent was synthesized by
stirring 2.5 h at r.t. The reaction with the formed organozinc reagent was stirred
at r.t. for 46.5 h and the reaction with the alcohol was stirred at r.t. for 21.5
h. After extractive workup, the excess of 2-ethyl-1-hexanol was removed using a short-path
vacuum distillation apparatus at 150 °C. The resulting crude product was purified
by column chromatography (silica gel; CH2 Cl2 /EtOAc; 8:2 v/v), providing the pure compound as a slightly yellowish liquid; yield:
1.77 g (42%).
IR (ATR): 2958, 2928, 1461, 1246, 1011, 869 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 3.98–3.85 (m, 4 H), 1.81–1.65 (m, 3 H), 1.55–1.50 (m, 2 H), 1.50–1.35
(m, 8 H), 1.35–1.17 (m, 16 H), 1.05–0.73 (m, 18 H).
13 C NMR (CDCl3 , 100 MHz): δ = 67.5, 67.4, 40.5, 40.4, 34.3, 34.3, 33.8, 33.7, 30.3, 30.2, 30.2,
29.1, 28.9, 28.7, 26.9, 26.8, 23.5, 23.5, 23.2, 23.1, 14.3, 14.2, 11.1, 10.5.
31 P NMR (CDCl3 , 162 MHz): δ = 32.9.
MS (ESI): m /z = 419 [M + H]+ , 441 [M + Na]+ , 837 [2 M + H]+ , 859 [2 M + Na]+ .
Anal. Calcd for C24 H51 O3 P: C, 68.86; H, 12.28. Found: C, 69.30; H, 12.22.
Dioctyl Phenylphosphonate (2d)
Dioctyl Phenylphosphonate (2d)
[CAS Reg. No. 1754-47-8]
Prepared according to the general phosphonate synthesis procedure using anhyd Et2 O (40 mL), phenylmagnesium bromide (3.3 mL, 10 mmol, 1 equiv), and 1-octanol (4.7
mL, 30 mmol, 3 equiv). The corresponding organozinc reagent was synthesized by stirring
2 h at r.t. The reaction with the formed organozinc reagent was stirred at r.t. for
21.5 h and the reaction with the alcohol was stirred at r.t. for 29 h. After extractive
workup, the excess of 1-octanol was removed using a short-path vacuum distillation
apparatus at 250 °C. The resulting crude product was purified by column chromatography
(silica gel; CH2 Cl2 /EtOAc; 95:5 v/v), providing the pure compound as a slightly yellowish liquid; yield:
0.55 g (14%).
IR (ATR): 2924, 2855, 1439, 1251, 1131, 977, 748, 695, 564 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.87–7.74 (m, 2 H), 7.58–7.51 (m, 1 H), 7.51–7.42 (m, 2 H), 4.11–3.95
(m, 4 H), 1.71–1.62 (m, 4 H), 1.39–1.31 (m, 4 H), 1.31–1.20 (m, 16 H), 0.87 (t, J = 6.9 Hz, 6 H).
13 C NMR (CDCl3 , 100 MHz): δ = 132.5, 132.4, 132.0, 131.9, 129.5, 128.6, 128.5, 127.7, 66.3, 66.2,
31.9, 30.6, 30.6, 29.3, 29.2, 25.7, 22.8, 14.2.
31 P NMR (CDCl3 , 162 MHz): δ = 18.9.
MS (ESI): m /z = 383 [M + H]+ , 405 [M + Na]+ , 765 [2 M + H]+ , 787 [2 M + Na]+ .
Anal. Calcd for C22 H39 O3 P: C, 69.08; H, 10.28. Found: C, 69.94; H, 10.43.
Bis(2-ethylhexyl) Octylphosphonate (2e)
Bis(2-ethylhexyl) Octylphosphonate (2e)
[CAS Reg. No. 52894-02-7]
Prepared according to the general phosphonate synthesis procedure using anhyd Et2 O (20 mL), octylmagnesium bromide (5 mL, 10 mmol, 1 equiv), and 2-ethyl-1-hexanol
(4.7 mL, 30 mmol, 3 equiv). The corresponding organozinc reagent was synthesized by
stirring 2 h at r.t. The reaction with the formed organozinc reagent was stirred at
r.t. for 24 h and the reaction with the alcohol was stirred at r.t. for 25 h. After
extractive workup, the excess of 2-ethyl-1-hexanol was removed using a short-path
vacuum distillation apparatus at 150 °C. The resulting crude product was purified
by column chromatography (silica gel; CH2 Cl2 /EtOAc; 95:5 v/v), providing the pure compound as a slightly yellowish liquid; yield:
1.82 g (43%).
IR (ATR): 2926, 2858, 1461, 1248, 1010, 863 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 3.98–3.84 (m, 4 H), 1.77–1.67 (m, 2 H), 1.63–1.50 (m, 4 H), 1.45–1.34
(m, 6 H), 1.33–1.20 (m, 20 H), 0.97–0.82 (m, 15 H).
13 C NMR (CDCl3 , 100 MHz): δ = 67.7, 67.6, 40.4, 40.4, 32.0, 30.8, 30.7, 30.1, 29.2, 29.2, 29.1,
26.2, 24.8, 23.5, 23.5, 23.1, 22.8, 22.7, 22.6, 14.2, 14.2, 11.1.
31 P NMR (CDCl3 , 162 MHz): δ = 32.7.
MS (ESI): m /z = 419 [M + H]+ , 441 [M + Na]+ , 837 [2 M + H]+ , 859 [2 M + Na]+ .
Anal. Calcd for C24 H51 O3 P: C, 68.86; H, 12.28. Found: C, 69.27; H, 12.14.
Octylphosphonic Acid (2f)
Octylphosphonic Acid (2f)
[CAS Reg. No. 4724-48-5]
To an oven-dried 100 mL two-neck flask, fitted with a reflux condenser were added
anhyd ZnCl2 (0.75 g, 5.5 mmol, 0.65 equiv) and anhyd Et2 O (20 mL). The mixture was cooled in an ice-bath and octylmagnesium bromide (4.2 mL,
8.4 mmol, 1 equiv) was slowly added. The reaction mixture was stirred 10 more min
at 0 °C followed by 2 h at r.t. The solution was then cooled in an ice-salt mixture
and POCl3 (0.78 mL, 8.4 mmol, 1 equiv) was added. After stirring with cooling for 5 min, the
mixture was brought to r.t. and stirred for 20 h. The mixture was cooled again in
an ice-salt mixture and H2 O (5 mL) was slowly added. Stirring with cooling for 5 min was followed by reaction
at r.t. for 25.5 h. The crude mixture was then poured into CH2 Cl2 (100 mL), washed three times with dil HCl (1–2%, 100 mL in total), dried (MgSO4 ), filtered, and evaporated to dryness. The resulting crude product was purified by
recrystallization from hot heptane (50 mL), filtered and washed with pentane, providing
the pure compound as a white solid; yield: 0.49 g (30%); mp 100–102 °C.
IR (ATR): 2918, 1468, 1106, 994, 943, 778, 715 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 9.53 (s, 2 H), 1.81–1.68 (m, 2 H), 1.68–1.55 (m, 2 H), 1.41–1.33 (m,
2 H), 1.33–1.22 (m, 8 H), 0.88 (t, J = 6.8 Hz, 3 H).
13 C NMR (CDCl3 , 100 MHz): δ = 31.9, 30.7, 30.5, 29.2, 29.2, 26.1, 24.7, 22.8, 22.2, 22.1, 14.2.
31 P NMR (CDCl3 , 162 MHz): δ = 37.7.
MS (ESI): m /z = 193 [M – H]– , 387 [2 M – H]– , 581 [3 M – H]– , 603 [3 M – 2 H + Na]– , 797 [4 M – 2 H + Na]– .
Anal. Calcd for C8 H19 O3 P: C, 49.48; H, 9.86. Found: C, 49.19; H, 9.71.
