New double-chain and aromatic (α-hydroxyalkyl)phosphorus amphiphiles

Article abstract of DOI:10.1055/s-2002-33111

New double-chain bis-(α-hydroxyalkyl)phosphinic acids 1 are synthesized from NaH₂PO₂·H₂O and aliphatic aldehydes. Direct and quantitative one-pot synthesis of new 4-alkoxybenzaldehydes 2 is realized from 1-bromoalkanes and

Full text of DOI:10.1055/s-2002-33111

PAPER
1385
New Double-Chain and Aromatic ( -Hydroxyalkyl)phosphorus Amphiphiles
New
D
ouble-Chain
l
and A
i
romati
c
c
(
-Hydr
o
e
xyalkyl)phosphor
B
us
A
mphiphiles run,*1 Guita Etemad-Moghadam2
Laboratoire des IMRCP, UMR CNRS 5623, Université Paul Sabatier, 118, route de Narbonne, Bât. 2R1, 31062 Toulouse Cedex 04, France
Fax +33(5)61558155; E-mail: alice.brun@mpikg.golm.mpg.de
Received 5 March 2002; revised 5 April 2002
alkyl)phosphinic and -phosphonic acid amphiphiles of
Abstract: New double-chain bis-( -hydroxyalkyl)phosphinic acids
different head-group polarity have been synthesized.11,12
These surfactants self-organize in aqueous media in mi-
celles and lyotropic liquid crystals and are able to form
1 are synthesized from NaH2PO2 H2O and aliphatic aldehydes. Di-
rect and quantitative one-pot synthesis of new 4-alkoxybenzal-
dehydes
2
is realized from 1-bromoalkanes and 4-
hydroxybenzaldehyde. Addition of NaH2PO2 H2O to aldehydes 2 stable and compact monolayers at the air/water interface
only when they possess a sufficiently long alkyl chain.12
leads to the formation of the bis-adducts and also to the cleavage of
the ether bond. New [ -hydroxy-(4-alkoxybenzyl)]phosphinic ac-
To the best of our knowledge, no other ( -hydroxy-
ids 3 are prepared by addition of aldehydes 2 to aqueous hypophos-
alkyl)phosphinic acid amphiphiles have been described
phorous acid.
since then. With a view to study the influence of hydro-
phobicity on the molecular aggregation properties of this
new class of surfactants, we decided to prepare new dou-
Key words: aldehydes, surfactants, phosphorylations, phosphinic
acids, benzaldehydes, addition reactions
ble-chain and aromatic ( -hydroxyalkyl)phosphorus am-
phiphiles.
( -Hydroxyalkyl)phosphoryl derivatives (phosphinic and
Our previous work on the synthesis of ( -hydroxy-
phosphonic acids, esters and salts) have potential biologi-
alkyl)phosphinic acids from 50% aqueous hypophospho-
cal activities such as enzyme and metalloenzyme inhibi-
rous acid and various aldehydes showed that the mono-
tors,3 bone resorption inhibitors,4 anti-viral, anti-tumoral
adduct is usually obtained as the main product accompa-
and anti-bacterial agents, or fungicides.5 These com-
nied by 5% of the bis-adduct in the case of aliphatic alde-
pounds may also be used as precursors for the synthesis of
hydes and 15% to 25% of the bis-adduct in the case of
organophosphorus polymers possessing flame-resistant,
aromatic aldehydes (Scheme 1).11,13
corrosion-resistant and ion-exchange properties.6 Indeed,
To prepare phosphorus double-chain amphiphiles, the
double addition of long chain aldehydes was realized on
sodium hypophosphite, a crystalline commercial com-
pound which allows reaction in more concentrated media
compared to 50% aqueous hypophosphorous acid previ-
ously used for the synthesis of the corresponding single-
chain analogs (Scheme 1). Reaction of monohydrated so-
dium hypophosphite, NaH2PO2 H2O with 2.5 equivalents
of long chain aldehyde in the presence of 2 equivalents of
hydrochloric acid in dioxane under reflux leads after 24
hours to bis-( -hydroxyalkyl)phosphinic acids 1a–c bear-
ing two alkyl chains (Schemes 2 and 3).
( -hydroxyalkyl)phosphinic and -phosphonic acids are
also used as extractants for the recovery or separation of
some metal ions.6,7 The presence of a hydrophobic moiety
must then widen their application field, biological and co-
ordinating properties being enhanced by the coexistence
of hydrophobic and hydrophilic groups in the molecule.
Furthermore, synthetic long-chain phosphinate and phos-
phonate esters, which can be considered as analogs of
phospholipids (the main components of biological mem-
branes), have applications as models of natural mem-
branes,8 enhancers of the transdermal penetration of
drugs,9 or for the vectorisation of anti-cancerous drugs.10
In the laboratory, new single-chain ( -hydroxy-
Scheme 1 Synthesis of ( -hydroxyalkyl)phosphinic acids from hypophosphorous acid and aliphatic or aromatic aldehydes.
Synthesis 2002, No. 10, 30 07 2002. Article Identifier:
1437-210X,E;2002,0,10,1385,1390,ftx,en;Z04402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1386
A. Brun, G. Etemad-Moghadam
PAPER
Scheme 2 Synthesis of bis-( -hydroxyalkyl)phosphinic acids 1 from sodium hypophosphite and aliphatic aldehydes.
Table 1 Yields and NMR Parameters of Bis-( -hydroxyalkyl)phos-
phinic Acids 1
Compounds 1a–c were obtained with 40% yield. Actual-
ly, prolonged heating leads also to the competitive oxida-
tion of the intermediate phosphinic acid P–H bond, to give
the corresponding phosphonic acid (Scheme 3). The syn-
thesis of ( -hydroxyalkyl)phosphonic acids was de-
scribed elsewhere.11
b
Compnd
No.
(31P)a
(13C) (1JCP
)
(1H)b
Yield (%)c
1a
1b
1c
40.4
68.77 (101.8)
68.64 (102.5)
3.77
41
44
40
The 31P NMR spectrum of the crude reaction mixture
shows two signals for bis-( -hydroxyalkyl)phosphinic ac-
ids 1a–c. Due to the presence of two stereogenic carbons
bonded to the phosphorus atom, and the phosphorus atom
being itself a pseudo-asymmetric center,14 these com-
pounds exist in 3 diastereomeric forms: 2 meso and 1 ra-
cemic pair. However, the 31P NMR spectra of compounds
1a–c exhibit degeneracies due to the rapid prototropic
transfer of the acidic proton between phosphoryl (P=O)
and acidic (P–OH) sites and only two signals are observed
around 40 ppm, corresponding to the racemic form R,R/
S,S and the meso R,S.11,13 After purification, one signal
only may be observed (Table 1), probably due to a too
small magnetic difference or a too small chemical shift
difference between isomers to be detectable by NMR
analysis.
43.0
42.3
68.59 (101.6)
68.39 (103.1)
3.83
3.77
41.8
68.75 (98.7)
68.70 (102.3)
a 31P NMR chemical shifts in CDCl3 + 2 drops of CD3COOD.
b 13C and 1H NMR chemical shifts of the methyne protons in CDCl3
+ 2 drops of CD3COOD, J in Hz.
c Isolated yields.
Long chain aromatic aldehydes 2 were prepared from 4-
hydroxybenzaldehyde and 1-bromoalkanes following the
method described by Lindsey et al.15 The one-pot addition
of 4-hydroxybenzaldehyde to alkylbromide bearing vari-
ous chain lengths (10 to 18 carbons), in the presence of ex-
cess anhydrous potassium carbonate, in DMF, leads after
1.5 hour at 80 °C to aromatic aldehydes 2 (Scheme 4).
In all cases, the presence of the two diastereomers in the
final product was confirmed by 13C NMR analysis of bis-
( -hydroxyalkyl)phosphinic acids 1a–c and the presence
The compounds 2a–e are obtained in quantitative yields,
without any previous protection of the aldehyde moiety.
Results are shown in Table 2. The presence of the ether
of two doublets
Hz).
= 0.05–0.2 ppm ( 13C ~ 68, 1JCP ~ 100
Following the idea of preparing new ( -hydroxy-
alkyl)phosphorus amphiphiles of enhanced hydrophobic-
ity, bearing one or two alkyl chains, we decided to prepare
a new series of long chain aromatic aldehydes which
could be further used to prepare phosphorus amphiphiles
using the phosphorylation reactions described previously
(vide supra).
1
group (O–CH2) is confirmed by H NMR ( 1H ~ 4.00,
3JHH = 6.5 Hz) and 13C NMR ( 13C ~ 68) analysis. The
signals at 1H ~ 9.8 and 13C ~ 190 are consistent with
the presence of the aldehyde moiety.
For the synthesis of bis-[ -hydroxy-(4-alkoxyben-
zyl)]phosphinic acids, under the same reaction conditions
as for aliphatic aldehydes (cf Table 1), monohydrated so-
Scheme 3 Competitive reactions in the case of addition of sodium hypophosphite to aliphatic aldehydes.
Synthesis 2002, No. 10, 1385–1390 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
New Double-Chain and Aromatic ( -Hydroxyalkyl)phosphorus Amphiphiles
1387
Scheme 4 Synthesis of 4-alkoxybenzaldehydes 2 from 1-bromoalkanes and 4-hydroxy-benzaldehyde.
bis-[ -hydroxy-(4-hydroxybenzyl)]phosphinic acids (
31P = 32.6 and 31.7) also occurs at the same time, these
compounds being the main products. Long heating under
reflux induced the cleavage of the ether group and conse-
quently the loss of the long alkyl chain(s). Actually, it was
shown previously that cleavage of ethers could be
achieved with aqueous hydrochloric acid in the presence
of surfactants, leading to the corresponding alkyl chlo-
rides.16 This type of micellar-catalyzed reaction can be
transposed to our case with respect to the amphiphilic na-
ture of our reactants and adducts. Our attempts to catalyze
the addition of sodium hypophosphite on 4-alkoxybenzal-
dehydes by another acid such as sulfuric acid remained
unsuccessful.
Table 2 Yields and NMR Parameters of 4-Alkoxybenzaldehydes 2
a
Compnd
No.
(1H) (3JHH
)
(13C)a
(1H)b
(13C)b
Yield
(%)c
2a
2b
2c
2d
2e
3.81 (6.4)
4.02 (6.5)
4.00 (6.5)
4.01 (6.4)
4.02 (6.5)
68.2
9.86
190.2
91
90
96
88
81
68.4
68.4
68.4
68.5
9.86
9.85
9.85
9.87
190.8
190.8
190.7
190.8
a 1H and 13C NMR chemical shifts of the O–CH2 moiety in CDCl3,
J in Hz.
b 1H and 13C NMR chemical shifts of the aldehyde group in CDCl3.
c Isolated yields.
We finally used the 4-alkoxybenzaldehydes 2a–e to pre-
pare single-chain -hydroxy-(4-alkoxybenzyl)]phosphin-
ic acid amphiphiles of enhanced hydrophobicity
compared to ( -hydroxyalkyl)phosphinic and -phosphon-
ic acids previously prepared in the laboratory.11,12 We
used the same protocol as for aliphatic aldehydes: 50%
dium hypophosphite was added to 2.5 equivalents of 4-
tetradecyloxybenzaldehyde 2c and heated under reflux
(Scheme 5).
31P{1H} NMR analysis of the reaction mixture shows two aqueous hypophosphorous acid was added to aromatic al-
signals at 31P = 38.3 and 36.9 corresponding to the two dehydes 2a–e (Scheme 6).
bis-[ -hydroxy-(4-tetradecyloxybenzyl)]phosphinic acid
The reaction was carried out under heating but for a limit-
diastereomers (cf. II). However, formation of mono-
ed time of 2 hours due to the possibility of cleavage of the
substituted
[ -hydroxy-(4-hydroxybenzyl)]phosphinic
ether bond in the presence of hydrochloric acid (vide su-
pra). New [ -hydroxy-(4-alkoxybenzyl)]phosphinic acids
1
acid ( 31P = 26.3, JPH = 582 Hz) and bis-substituted
Scheme 5 Synthesis of bis-[ -hydroxy-(4-tetradecyloxybenzyl)]phosphinic acid from sodium hypophosphite and 4-tetradecyloxybenzalde-
hyde.
Scheme 6 Synthesis of [ -hydroxy-(4-alkoxybenzyl)]phosphinic acids 3 from hypophosphorous acid and 4-alkoxybenzaldehydes 2.
Synthesis 2002, No. 10, 1385–1390 ISSN 0039-7881 © Thieme Stuttgart · New York

1388
A. Brun, G. Etemad-Moghadam
PAPER
1-Bromoalkanes C10 (Acros), C12, C14 (Aldrich) and C16, C18 (Lan-
caster), 4-hydroxybenzaldehyde (Aldrich), 50% aq hypophospho-
rous acid (Aldrich), aliphatic aldehydes (C10–C14) (Aldrich) and
monohydrated sodium hypophosphite (Aldrich) were used as re-
ceived without further purification. DMF was maintained over 4 Å
molecular sieves and stored in dark bottles protected from moisture.
K2CO3 was dried at 80 °C over night before use.
3a–e were consequently obtained in moderate yields
(30% to 50%). Results are reported in Table 3.
In the 31P NMR spectra of compounds 3a–e we observe a
doublet at 31P ~ 29.7 (1JPH ~ 525 Hz) consistent with the
presence of a phosphinic acid moiety. The ether moiety
(O–CH2) resonates at 13C ~ 67 and 1H ~ 3.95, confirm-
ing the conservation of the long alkyl chain.
The purity of materials was assessed by elemental microanalysis,
1H, 13C and 31P NMR, IR and mass spectroscopy. Yields indicated
correspond to pure products.
New double-chain bis-( -hydroxyalkyl)phosphinic acids
were prepared from aliphatic aldehydes and sodium hypo-
phosphite NaH2PO2 H2O under prolonged heating. The
same reaction carried out with new 4-alkoxybenzalde-
hydes, quantitatively prepared by an one-pot reaction,
also leads to the bis-adducts but in very poor yields due to
the cleavage of the ether bond in hydrochloric acid and
micellar media. Finally, a new series of [ -hydroxy-(4-
alkoxybenzyl)]phosphinic acids bearing a 10 to 18 carbon
single chain was synthesized from 4-alkoxybenzalde-
hydes and 50% aqueous hypophosphorous acid under lim-
ited heating.
Bis-( -hydroxyalkyl)phosphinic acids 1; General procedure
To a solution of NaH2PO2 H2O (0.5 g, 4.71 mmol) in dioxane (7
mL) was added long chain aldehyde (2.5 equiv) and aq HCl (37%)
(2 equiv). The mixture was heated under reflux for 24 hours, leading
to a brown solution which was then rotary evaporated. The obtained
residue was washed with H2O, THF and acetone to give a white
powder (after removing solvents), and finally recrystallized from
dioxane.
Bis-( -hydroxydecyl)phosphonic Acid (1a)
Yield: 41%; mp 198 °C (from dioxane – decomposition tempera-
ture observed by DSC).
The study of the molecular aggregation of these new dou-
ble-chain bis-( -hydroxyalkyl)phosphinic acids and sin-
gle-chain [ -hydroxy-(4-alkoxybenzyl)]phosphinic acids
is currently in progress. After studying the properties of
the ( -hydroxyalkyl)phosphinic and -phosphonic acids,12
we wish to compare the influence of an enhanced hydro-
phobicity, brought about either by an additional alkyl
chain or the introduction of an aromatic moiety, on the
formation of stable monolayers at the air/water interface
or on the formation of micelles, vesicles and lyotropic liq-
uid crystals in aqueous media.
IR (KBr): 1141.5 and 1123.8 (P=O), 958.3 (POH) cm–1.
1H NMR (250.13 MHz, CDCl3 + 2 drops of CD3COOD): = 3.77
(d, 2JHP = 10.0 Hz, 2 H), 1.48–1.16 (m, 32 H), 0.76 (t, 3JHH = 6.8 Hz,
6H).
13C NMR (100.61 MHz, CDCl3 + 2 drops of CD3COOD): = 68.8
(d, 1JCP = 102 Hz), 68.6 (d, 1JCP = 103 Hz), 31.9–22.6 (m), 13.9 (s).
31P NMR (81.01 MHz, CDCl3 + 2 drops of CD3COOD): = 40.4
(m).
MS (DCI/NH3): m/z = 379 (M + H)+, 396 (M + NH4)+.
Anal. Calcd for C20H43O4P: C, 63.46; H, 11.45. Found: C, 62.51; H,
11.10.
Spectra were recorded using the following instruments: IR spectra,
Bis-( -hydroxydodecyl)phosphonic Acid (1b)
Yield: 44%; mp 143 °C (from hexane, observed by DSC).
IR (KBr): 1142.4 (P=O), 963.0 (POH) cm–1.
1
Perkin-Elmer 225 or Perkin-Elmer IR-FT 1600; H, 13C and 31P
NMR spectra, Bruker AC80, AC200 or 250WM; mass spectra by
chemical ionization (DCI/NH3), Nermag R10-10H.
1H NMR (200.13 MHz, CDCl3 + 2 drops of CD3COOD): = 3.83
Melting points were measured in open glass capillaries with a Leitz
Biomed apparatus or by differential scanning calorimetry (DSC)
using a Perkin-Elmer Pyris 1 calorimeter.
(m, 2 H), 1.49–1.15 (m, 40 H), 0.76 (t, 3JHH = 6.6 Hz, 6 H).
13C NMR (50.32 MHz, CDCl3 + 2 drops of CD3COOD): = 68.6
(d, 1JCP = 102 Hz), 68.4 (d, 1JCP = 103 Hz), 31.8–22.5 (m), 13.8 (s).
Elemental analyses were performed by the Microanalytical Service
Laboratory of the ‘Laboratoire de Chimie de Coordination’ of
Toulouse.
31P NMR (81.01 MHz, CDCl3 + 2 drops of CD3COOD): = 43.0
and 42.3 (m).
Table 3 Yields and NMR Parameters of [ -Hydroxy-(4-alkoxybenzyl)]phosphinic Acids 3
a
b
b
Compd No.
(31P) (1JPH
29.7 (526)
29.6 (526)
29.7 (525)
29.7 (525)
29.7 (525)
)
(13C) (1JCP
)
(1H) (2JHP
4.66 (8.2)
4.65 (8.2)
4.66 (8.1)
4.65 (7.7)
4.65 (8.1)
)
(13C)c
67.3
(1H)c
3.94
Yield (%)d
3a
3b
3c
3d
3e
71.0 (110.4)
71.0 (110.5)
71.1 (109.0)
71.0 (109.0)
71.4 (109.0)
46
30
30
45
40
67.3
67.4
67.3
67.6
3.94
3.96
3.93
3.95
a 31P NMR chemical shifts in DMSO-d6, J in Hz.
b 13C and 1H NMR chemical shifts of the methyne proton in DMSO-d6, J in Hz.
c 13C and 1H NMR chemical shifts of (O–CH2) moiety in DMSO-d6.
d Isolated yields.
Synthesis 2002, No. 10, 1385–1390 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
New Double-Chain and Aromatic ( -Hydroxyalkyl)phosphorus Amphiphiles
1389
MS (DCI/NH3): m/z = 435 (M + H)+, 452 (M + NH4)+.
4-Hexadecyloxybenzaldehyde (2d)
Yield: 88%; mp 49–50 °C (from CH2Cl2); Rf (CH2Cl2) 0.56.
IR (KBr): 1690.2 (C=O), 1602.0 (C=C) cm–1.
Anal. Calcd for C24H51O4P: C, 66.32; H, 11.83. Found: C, 66.02; H,
12.38.
1H NMR (200.13 MHz, CDCl3): = 9.85 (s, 1 H), 7.80 (m, 2 H),
6.96 (m, 2 H), 4.01 (t, 3JHH = 6.4 Hz, 2 H), 1.79 (m, 2 H), 1.24 (m,
26 H), 0.86 (t, 3JHH = 6.5 Hz, 3 H).
13C NMR (50.32 MHz, CDCl3): = 190.7 (s), 164.3 (s), 132.0 (s),
114.7 (s), 129.8 (s), 68.4 (s), 32.0–22.7 (m), 14.1 (s).
Bis-( -hydroxytetradecyl)phosphonic Acid (1c)
Yield 40%; mp 136 °C (from hexane, observed by DSC).
IR (KBr): 1141.3 and 1071.2 (P=O), 958.3 (POH) cm–1.
1H NMR (200.13 MHz, CDCl3 + 2 drops of CD3COOD): = 3.77
(d, 2JHP = 11.8 Hz, 2 H), 1.55–1.21 (m, 48 H), 0.83 (m, 6 H).
MS (DCI/NH3): m/z = 347 (M + H)+, 364 (M + NH4)+.
13C NMR (62.89 MHz, CDCl3 + 2 drops of CD3COOD): = 68.8
(d, 1JCP = 99 Hz), 68.7 (d, 1JCP = 102 Hz), 31.8–22.6 (m), 13.9 (s).
4-Octadecyloxybenzaldehyde (2e)
Yield 81%; mp 52–54 °C (from CH2Cl2); Rf (CH2Cl2) 0.61.
IR (KBr): 1691.7 (C=O), 1601.6 (C=C) cm–1.
31P NMR (81.01 MHz, CDCl3 + 2 drops of CD3COOD): = 41.8
(m).
MS (DCI/NH3): m/z = 491 (M + H)+, 508 (M + NH4)+.
1H NMR (200.13 MHz, CDCl3): = 9.87 (s, 1 H), 7.81 (m, 2 H),
6.97 (m, 2 H), 4.02 (t, 3JHH = 6.5 Hz, 2 H), 1.80 (m, 2 H), 1.25 (m,
30 H), 0.87 (t, 3JHH = 6.2 Hz, 3 H).
13C NMR (50.32 MHz, CDCl3): = 190.8 (s), 164.3 (s), 132.0 (s),
114.8 (s), 129.8 (s), 68.5 (s), 32.0–22.7 (m), 14.2 (s).
Anal. Calcd for C28H59O4P: C, 68.53; H, 12.12. Found: C, 68.59; H,
12.27.
4-Alkoxybenzaldehydes 2; General Procedure
The reaction was carried out under an argon atmosphere. To a
stirred mixture of 4-hydroxybenzaldehyde (1.22 g, 1 equiv) and an-
hyd K2CO3 (7 g, 5 equiv) in anhyd DMF (30 mL) was added 1-bro-
moalkane (1 equiv). The mixture was stirred at 80 °C for 90 min,
allowed to cool to r.t. and then diluted with H2O (75 mL). After ex-
traction with EtOAc (4 30 mL), the combined organic phases
were washed with brine (100 mL), dried (MgSO4) and rotary evap-
orated. The resulting oily residue was finally purified on chromato-
graphic silica column eluted with CH2Cl2 leading to a yellow waxy
solid.
MS (DCI/NH3): m/z = 375 (M + H)+, 392 (M + NH4)+.
[ -Hydroxy-(4-alkoxybenzyl)]phosphinic Acids 3; General Pro-
cedure
A heterogeneous mixture of hypophosphorous acid (50% aq) (6.8
mmol), aldehyde (1 equiv) and aq HCl (37%) (0.05 mL) in dioxane
(6 mL) was stirred at 80 °C for 2 h. Solvents were rotary evaporated
and the residue was washed with distilled H2O, n-hexane, 2-pro-
panol and finally recrystallized from dioxane. The given white solid
was then filtered off and dried under vacuum.
4-Decyloxybenzaldehyde (2a)
Yield: 91%; Rf (CH2Cl2) 0.48.
IR (KBr): 1693.3 (C=O), 1601.2 (C=C) cm–1.
1H NMR (200.13 MHz, CDCl3): = 9.86 (s, 1 H), 7.62 (m, 2 H),
6.79 (m, 2 H), 3.81 (t, 3JHH = 6.4 Hz, 2 H), 1.62 (m, 2 H), 1.11 (m,
14 H), 0.73 (t, 3JHH = 7.1 Hz, 3 H).
13C NMR (50.32 MHz, CDCl3): = 190.2 (s), 164.1 (s), 131.7 (s),
114.6 (s), 129.7 (s), 68.2 (s), 31.9–22.6 (m), 14.0 (s).
[ -Hydroxy-(4-decyloxybenzyl)]phosphinic Acid (3a)
Yield: 46%; mp 107–117 °C (from dioxane).
IR (KBr): 2407.1 (PH), 1609.9 (C=C), 1156.3 and 1103.7
(P=O), 960.2 (POH) cm–1.
1H NMR (200.13 MHz, DMSO-d6): = 7.27 (m, 2 H), 6.89 (m, 2
H), 6.71 (d, 1JHP = 526 Hz, 1 H), 4.66 (d, 2JHP = 8.2 Hz, 1 H), 3.94
3
(t, JHH = 6.2 Hz, 2 H), 1.70 (m, 2 H), 1.26 (m, 14 H), 0.87 (t,
3JHH = 6.4 Hz, 3 H).
MS (DCI/NH3): m/z = 263 (M + H)+, 280 (M + NH4)+.
13C NMR (50.32 MHz, DMSO-d6): = 158.0 (s), 129.1 (s), 128.2
(s), 113.8 (s), 71.0 (d, 1JCP = 110 Hz), 67.3 (s), 31.2–22.0 (m), 13.9
4-Dodecyloxybenzaldehyde (2b)
(s).
Yield: 90%; mp 25–28 °C (from CH2Cl2); Rf (CH2Cl2) 0.53.
IR (KBr): 1694.8 (C=O), 1601.4 (C=C) cm–1.
1H NMR (200.13 MHz, CDCl3): = 9.86 (s, 1 H), 7.81 (m, 2 H),
6.97 (m, 2 H), 4.02 (t, 3JHH = 6.5 Hz, 2 H), 1.80 (m, 2 H), 1.25 (m,
18 H), 0.86 (t, 3JHH = 6.2 Hz, 3 H).
31P NMR (81.01 MHz, DMSO-d6): = 29.7 (d, 1JPH = 526 Hz).
MS (DCI/NH3): m/z = 330 (MH2)+, 346 (M + NH4)+.
Anal. Calcd for C17H29O4P: C, 62.18; H, 8.90. Found: C, 62.29; H,
8.73.
13C NMR (50.32 MHz, CDCl3): = 190.8 (s), 164.3 (s), 132.0 (s),
114.8 (s), 129.8 (s), 68.4 (s), 31.9–22.7 (m), 14.1 (s).
[ -Hydroxy-(4-dodecyloxybenzyl)]phosphinic Acid (3b)
Yield: 30%; mp 109–119 °C (from dioxane).
MS (DCI/NH3): m/z = 291 (M + H)+, 308 (M + NH4)+.
IR (KBr): 2409.1 (PH), 1609.4 (C=C), 1156.3 and 1103.0
(P=O), 960.1 (POH) cm–1.
4-Tetradecyloxybenzaldehyde (2c)
Yield: 96%; mp 39–40 °C (from CH2Cl2); Rf (CH2Cl2) 0.57.
IR (KBr): 1692.1 (C=O), 1601.5 (C=C) cm–1.
1H NMR (200.13 MHz, CDCl3): = 9.85 (s, 1 H), 7.79 (m, 2 H),
6.96 (m, 2 H), 4.00 (t, 3JHH = 6.5 Hz, 2 H), 1.79 (m, 2 H), 1.24 (m,
22 H), 0.86 (t, 3JHH = 6.6 Hz, 3 H).
1H NMR (200.13 MHz, DMSO-d6): = 7.27 (m, 2 H), 6.89 (m, 2
H), 6.72 (d, 1JHP = 526 Hz, 1 H), 4.65 (d, 2JHP = 8.2 Hz, 1 H), 3.94
3
(t, JHH = 6.2 Hz, 2 H), 1.70 (m, 2 H), 1.26 (m, 18 H), 0.87 (t,
3JHH = 6.4 Hz, 3 H).
13C NMR (50.32 MHz, DMSO-d6): = 158.0 (s), 129.1 (s), 128.2
(s), 113.8 (s), 71.0 (d, 1JCP = 111 Hz), 67.3 (s), 31.2–22.0 (m), 13.9
(s).
13C NMR (50.32 MHz, CDCl3): = 190.8 (s), 164.3 (s), 132.0 (s),
114.8 (s), 129.8 (s), 68.4 (s), 32.0–22.7 (m), 14.2 (s).
31P NMR (81.01 MHz, DMSO-d6): = 29.6 (d, 1JPH = 526 Hz).
MS (DCI/NH3): m/z = 358 (MH2)+, 374 (M + NH4)+.
MS (DCI/NH3): m/z = 319 (M + H)+, 336 (M + NH4)+.
Anal. Calcd for C19H33O4P : C, 64.02; H, 9.33. Found: C, 64.05; H,
9.21.
Synthesis 2002, No. 10, 1385–1390 ISSN 0039-7881 © Thieme Stuttgart · New York

1390
A. Brun, G. Etemad-Moghadam
PAPER
[ -Hydroxy-(4-tetradecyloxybenzyl)]phosphinic Acid (3c)
(3) (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.
Yield: 30%; mp 108–116 °C (from dioxane).
Tetrahedron Lett. 1990, 31, 5587. (b) Patel, D. V.; Rielly-
Gauvin, K.; Ryono, D. E. Tetrahedron Lett. 1990, 31, 5591.
(c) Stowasser, B.; Budt, K. H.; Jian-Qi, L.; Peyman, A.;
Ruppert, D. Tetrahedron Lett. 1992, 33, 1625. (d) Peyman,
A.; Budt, K. H.; Spanig, J.; Ruppert, D. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1720. (e) Black, R. M.; Harrison, J. M.
The Chemistry of Organophosphorus Compounds, Vol. 4;
Hartley, F. R., Ed.; Wiley: New York, 1996, 781; and
references cited therein.
IR (KBr): 2428.6 (PH), 1608.4 (C=C), 1173.9 (P=O), 1002.7 and
939.8 (POH) cm–1.
31P NMR (81.01 MHz, DMSO-d6): = 29.7 (d, 1JPH = 525 Hz).
1H NMR (200.13 MHz, DMSO-d6): = 7.29 (m, 2 H), 6.89 (m, 2
H), 6.71 (d, 1JHP = 526 Hz, 1 H), 4.66 (d, 2JHP = 8.1 Hz, 1 H), 3.96
(t, 3JHH = 6.4 Hz, 2 H), 1.71 (m, 2 H), 1.27 (m, 22 H), 0.87 (m, 3 H).
13C NMR (50.32 MHz, DMSO-d6): = 158.1 (s), 129.2 (s), 128.2
(4) (a) Ruel, R.; Bouvier, J.-P.; Young, R. N. J. Org. Chem.
1995, 60, 5209. (b) Page, P. C. B.; Moore, J. P. G.;
Mansfield, I.; McKenzie, M. J.; Bowler, W. B.; Gallagher, J.
A. Tetrahedron 2001, 57, 1837.
(s), 113.8 (s), 71.1 (d, 1JCP = 109 Hz), 67.4 (s), 31.2–21.9 (m), 13.8
(s).
MS (DCI/NH3): m/z = 386 (MH2)+, 402 (M + NH4)+.
(5) (a) Einhäuser, Th. J.; Galanski, M.; Vogel, E.; Keppler, B. K.
Inorg. Chim. Acta 1997, 257, 265. (b) Kalir, A.; Kalir, H. H.
The Chemistry of Organophosphorus Compounds, Vol. 4;
Hartley, F. R., Ed.; Wiley: New York, 1996, 767; and
references cited therein. (c) Fields, S. C. Tetrahedron 1999,
55, 12237; and references cited therein. (d) Baylis, E. K.
Eur. Pat. Appl. EP 614900, 1994. (e) Budavari, S. Merck
Index, 11th Ed.; Merck Rahway: NJ, 1989, 665; (no. 4169).
(f) Hidaka, T.; Iwakura, H.; Imai, S.; Soto, H. J. Antibiot.
1992, 45, 1008. (g) Shiraki, K.; Okuno, T.; Yamanishi, K.;
Takahashi, M. Antiviral Res. 1989, 12, 311. (h) Hudson, H.
R.; Ismail, F.; Pianka, M. Phosphorus, Sulfur Silicon Relat.
Elem. 2001, 173, 143.
(6) (a) Petrov, K. A.; Parshina, V. A. Russ. Chem. Rev. 1968, 37,
532; and references cited therein. (b) Kerr, E. A.; Rideout, J.
Eur. Pat. Appl. EP 516,346, 1992. (c) Telegdi, J.; Shaglouf,
M. M.; Shaban, A.; Karman, F. H.; Betroti, I.; Mohai, M.;
Kalman, E. Electrochim. Acta 2001, 46, 3791.
(7) (a) Herranz, C. Tenside Detergents 1981, 18, 190.
(b) Herranz, C.; Martinez, M. J. J. Disp. Sci. Technol. 1988,
9, 209. (c) Martinez, M.; Herranz, C.; Miralles, N.; Sastre,
A. J. Disp. Sci. Technol. 1995, 16, 221. (d) Martinez, M.;
Miralles, N.; Sastre, A.; Herranz, C. Hydrometallurgy 1993,
33, 95.
(8) (a) Kunitake, T.; Okahata, Y. Bull. Chem. Soc. Jpn. 1978,
51(6), 1877. (b) Wagenaar, A.; Rupert, L. A. M.; Engberts,
J. B. F. N.; Hoekstra, D. J. Org. Chem. 1989, 54, 2638.
(c) Walde, P.; Wessicken, M.; Rädler, U.; Berclaz, N.;
Conde-Frieboes, K.; Luisi, P. L. J. Phys. Chem. B 1997, 101,
7390.
(9) Aoyagi, T.; Yamamura, M.; Matsui, K.; Nagase, Y. Drug
Des. Discov. 1991, 8, 47.
(10) Einhäuser, Th. J.; Galanski, M.; Vogel, E.; Keppler, B. K.
Inorg. Chim. Acta 1997, 257, 265.
Anal. Calcd for C21H37O4P: C, 65.60; H, 9.70. Found: C, 65.52; H,
10.10.
[ -Hydroxy-(4-hexadecyloxybenzyl)]phosphinic Acid (3d)
Yield: 45%; mp 110–113 °C (from acetone).
IR (KBr): 2434.5 (PH), 1608.5 (C=C), 1174.0 (P=O), 1004.0
(POH) cm–1.
31P NMR (81.01 MHz, DMSO-d6): = 29.7 (d, 1JPH = 525 Hz).
1H NMR (200.13 MHz, DMSO-d6): = 7.26 (m, 2 H), 6.88 (m, 2
H), 6.70 (d, 1JHP = 525 Hz, 1 H), 4.65 (d, 2JHP = 7.7 Hz, 1 H), 3.93
(t, 3JHH = 5.6 Hz, 2 H), 1.69 (m, 2 H), 1.24 (m, 26 H), 0.85 (m, 3 H).
13C NMR (50.32 MHz, DMSO-d6): = 158.0 (s), 129.2 (s), 128.3
(s), 113.8 (s), 71.0 (d, 1JCP = 109 Hz), 67.3 (s), 31.2-22.0 (m), 13.9
(s).
MS (DCI/NH3): m/z = 414 (MH2)+, 430 (M + NH4)+.
Anal. Calcd for C23H41O4P: C, 66.96; H, 10.01. Found: C, 66.95; H,
10.01.
[ -Hydroxy-(4-octadecyloxybenzyl)]phosphinic Acid (3e)
Yield: 40%; mp 108-120 °C (from dioxane).
IR (KBr): 2363.4 (PH), 1610.6 (C=C), 1156.6 and 1101.9
(P=O), 961.6 (POH) cm–1.
1H NMR (200.13 MHz, DMSO-d6): = 7.29 (m, 2 H), 6.87 (m, 2
2
H), 6.74 (d, 1JHP = 526 Hz, 1 H), 4.65 (d, JHP = 8.1 Hz, 1 H), 3.95
3
(t, JHH = 6.4 Hz, 2 H), 1.70 (m, 2 H), 1.20 (m, 30 H), 0.87 (t,
3JHH = 6.2 Hz, 3 H).
13C NMR (50.32 MHz, DMSO-d6): = 158.1 (s), 129.4 (s), 128.1
(s), 113.9 (s), 71.4 (d, 1JCP = 109 Hz), 67.6 (s), 31.2–21.9 (m), 13.6
(s).
31P NMR (81.01 MHz, DMSO-d6): = 29.7 (d, 1JPH = 525 Hz).
MS (DCI/NH3): m/z = 442 (MH2)+, 458 (M + NH4)+.
(11) Albouy, D.; Brun, A.; Munoz, A.; Etemad-Moghadam, G. J.
Org. Chem. 1998, 63, 7223.
(12) Brun, A.; Albouy, D.; Perez, E.; Rico-Lattes, I.; Etemad-
Moghadam, G. Langmuir 2001, 17, 5208.
Anal. Calcd for C25H45O4P: C, 68.15; H, 10.29. Found: C, 68.62; H,
9.94.
(13) Albouy, D.; Etemad-Moghadam, G.; Koenig, M. Eur. J.
Org. Chem. 1999, 861.
References
(14) (a) Majewski, P. Synthesis 1987, 555. (b) Eliel, E. L.;
Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley-Interscience: New York, 1994, 67.
(c) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry
of Organic Compounds; Wiley-Interscience: New York,
1994, 123. (d) Eliel, E. L.; Wilen, S. H.; Mander, L. N.
Stereochemistry of Organic Compounds; Wiley-
Interscience: New York, 1994, 230.
(1) New address: Alice Brun, Max-Planck-Institute of Colloids
and Interfaces, 14424 Potsdam, Germany; fax
+49(331)5679202; e-mail alice.brun@mpikg-golm.mpg.de
(2) Deceased 07.03.2002.
(15) Wagner, R. W.; Lindsey, J. S.; Turowska-Tyrk, I.; Scheidt,
W. R. Tetrahedron 1994, 50, 11097.
(16) Jursic, J. J. Chem. Res., Synop. 1989, 284.
Synthesis 2002, No. 10, 1385–1390 ISSN 0039-7881 © Thieme Stuttgart · New York