Optimization and a Kinetic Study on the Acidic Hydrolysis of Dialkyl α-Hydroxybenzylphosphonates

Article abstract of DOI:10.3390/molecules25173793

The two-step acidic hydrolysis of α-hydroxybenzylphosphonates and a few related derivatives was monitored in order to determine the kinetics and to map the reactivity of the differently substituted phosphonates in hydrolysis. Electron-withdrawing substituents increased the rate, while electron-releasing ones slowed down the reaction. Both hydrolysis steps were characterized by pseudo-first-order rate constants. The fission of the second P-O-C bond was found to be the rate-determining step.

Full text of DOI:10.3390/molecules25173793

molecules
Article
Optimization and a Kinetic Study on the Acidic
Hydrolysis of Dialkyl α-Hydroxybenzylphosphonates
Nikoletta Harsági 1, Zita Rádai 1, Áron Szigetvári 2, János Kóti 2 and György Keglevich 1,
*
1
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics,
1521 Budapest, Hungary; harsagi.nikoletta@mail.bme.hu (N.H.); radai.zita@mail.bme.hu (Z.R.)
Gedeon Richter Plc., 1475 Budapest, Hungary; szigetvaria@richter.hu (Á.S.); j.koti@richter.hu (J.K.)
Correspondence: gkeglevich@mail.bme.hu; Tel.: +36-1-463-1111/5883
2
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Academic Editors: Milos Sedlak
Received: 14 July 2020; Accepted: 17 August 2020; Published: 20 August 2020
Abstract: The two-step acidic hydrolysis of
α-hydroxybenzylphosphonates and a few related
derivatives was monitored in order to determine the kinetics and to map the reactivity of the
differently substituted phosphonates in hydrolysis. Electron-withdrawing substituents increased the
rate, while electron-releasing ones slowed down the reaction. Both hydrolysis steps were characterized
by pseudo-first-order rate constants. The fission of the second P-O-C bond was found to be the
rate-determining step.
Keywords: dialkyl
α-hydroxyphosphonates; hydrolysis; phosphonic ester–acid intermediate;
phosphonic acid; rate constants; mechanism
1. Introduction
The hydrolysis of P-esters (e.g., phosphinates and phosphonates) resulting in the formation
of the corresponding acids (phosphinic acids and phosphonic acids, respectively) is an important
chemical transformation, and hence it is applied widely in syntheses. Most often, the hydrolyses were
performed under acidic conditions [
1–4
], but the application of NaOH or KOH is also common [
5–8].
An additional possibility is the fission of the P-O-C unit by the effect of Me3SiBr [
9–
11]. Usually,
the acid- or base-catalyzed hydrolyses were carried out routinely, under “excessive” (unoptimized)
conditions applying the acid or base catalysts in a larger quantity than required, and allowing
longer reaction times. We undertook to explore the optimum conditions for the HCl-catalyzed
hydrolysis of phosphinic and phosphonic esters. In the first round, the acid-catalyzed hydrolysis of
cyclic phosphinates, such as 1-alkoxy-3-phospholene oxides, 1-alkoxyphospholane oxides, and an
1-alkoxy-1,2,3,4,5,6-hexahydrophosphinine oxide was investigated, optimized, and characterized by
rate constants [12]. Then, the hydrolysis of a series of dialkyl arylphosphonates was studied. In this case,
two-step conversions were monitored and quantified by k values [13].
obtained in the Pudovik reaction of substituted benzaldehydes and dialkyl phosphites, form a
representative class of phosphonic acid derivatives [14]. -Hydroxyphosphonates are versatile
intermediates that may be transformed to -aminophosphonates [15], can be phosphorylated [16],
and may be rearranged to the corresponding phosphates [17]. The catalytic hydrogenation of -dibenzyl
hydroxyphosphonates afforded the respective -hydroxyphosphonic acids [18]. Moreover, they may
α-Hydroxybenzylyphosphonates,
α
α
α
α
be of cytotoxic activity [18]. In this article, we describe our results on the HCl–promoted hydrolysis of
α-hydroxyphosphonates and a few related analogues.
2. Results and Discussion
Substituted
α-hydroxybenzylphosphonates (1a–j) prepared as described earlier [18] were subjected
to acidic hydrolysis. The application of three equivalents (0.5 mL) of concentrated hydrochloric acid in
Molecules 2020, 25, 3793; doi:10.3390/molecules25173793
www.mdpi.com/journal/molecules

Molecules 2020, 25, 3793
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1 mL of water for ca. 2 mmol of the phosphonate (1) at reflux resulted in complete hydrolysis within
2.5–9.5 h depending on the substituents. The reactions followed a two-step protocol and took place via
the corresponding ester–acid intermediate
, and were monitored by 31P NMR spectroscopy (Scheme 1).
Experimental data together with the calculated pseudo-first-order k1 and k2 rate constants are listed in
2
Table 1, while the concentration–time diagrams exhibiting the relative proportions of components 1, 2,
and 3 are shown in Figures 1 and 2 and Figures S1–S8 in the Supplementary Materials.
OH
OH
OH
O
O
O
H2O /cc.HCl
H2O/ cc.HCl
P
P
P
OR
OH
OH
k1
k2
RO
RO
HO
Y
Y
Y
1
2
3
Scheme 1. Two-step acidic hydrolysis of substituted
α-hydroxybenzylphosphonates. For the Y
substituents see Table 1.
Table 1. Experimental and kinetic data on the two-step hydrolysis of
1a–j.
α
-hydroxybenzylphosphonates
k1 (h−1
)
k2 (h−1
)
Entry
Y
R
tmax (min)
tr (h)
R2
1
2
3
4
5
6
7
8
9
H (a)
NO2 (b)
Cl (c)
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
44
22
34
32
51
76
90
75
60
80
6.5
2.5
5.5
6.0
5.5
8
9.5
5.5
8.0
9.0
2.64
5.18
3.36
3.93
2.03
1.64
1.03
1.40
1.08
1.35
0.60
1.24
0.79
0.67
0.61
0.31
0.35
0.61
0.42
0.31
0.994
0.989
0.987
0.965
0.988
0.962
0.986
0.992
0.992
0.970
F (d)
CF3 (e)
Me (f)
H (g)
NO2 (h)
Cl (i)
10
F (j)
Figure 1. Concentration profile for the components during the hydrolysis of dimethyl
α-
hydroxybenzylphosphonate (1a) under optimum conditions. The R2 measure of goodness of fit
is 0.994.

Molecules 2020, 25, 3793
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Figure 2.
Concentration profile for the components during the hydrolysis of diethyl α-
hydroxybenzylphosphonate (1g) under optimum conditions. The R2 measure of goodness of fit
is 0.986.
One can see that the hydrolysis of the unsubstituted dimethyl
was complete after tr = 6.5 h, and the maximum proportion of intermediate 2a could be observed
at max = 44 min
In this case, k1 and k2 were found to be 2.64 h−1 and 0.60 h−1, respectively
Table 1/Entry 1). Electron-withdrawing substituents, such as 4-NO2, 4-Cl and 4-F in the phenyl ring
facilitated the hydrolyses that were complete after 2.5 h, 5.5 h, and 6 h, respectively. The maximum
concentration of intermediates 2b appeared in the range of 22–34 min. The k1 values fell in the
α-hydroxybenzylphosphonate
t
.
(
–
d
range of 3.36–5.18 h−1, while the k2 constants were between 0.67 and 1.24 h−1 (Table 1/Entries 2–4).
It seems that the 4-CF3Ph substituent acted overall as the 4-ClPh group, as marked by tr = 5.5 h. In this
case (Y = CF3), k1 was 2.03, while k2 was 0.61 (Table 1/Entry 5). In the above series, the hydrolysis of
the 4-Me-substituted benzylphosphonate (1f) was the slowest, as a complete hydrolysis required 8
h, and the rate constants were found to be 1.64 (k1) and 0.31 (k2) (Table 1/Entry 6). It is noteworthy
that the fission of the second P–OMe unit is the rate-determining step. As can be seen from Table 1,
the k1 values for the above cases are, in almost all cases, more than four times larger as compared to
the k2 values.
Regarding the series of substituted diethyl
α-hydroxybenzylphosphonates (1g–j), the hydrolysis
of the unsubstituted model (1g) was significantly slower than that of the dimethyl analogue (1a
)
(compare the reaction times of 9.5 h (Table 1/Entry 7) and 6.5 h (Table 1/Entry 1)). The corresponding k1
and k2 rate constants for the hydrolysis of diethyl ester 1g were roughly the half the ones obtained for
the methyl counterpart (1a) (compare rate constants 1.03/0.35 versus 2.64/0.60 (Table 1/Entry 7 versus
Entry 1). Hydrolysis of the α-hydroxyphosphonates with electron-withdrawing 4-NO2, 4-Cl, and 4-F
substituents in the phenyl ring (1h-j) required shorter reaction times of 5.5–9.0 h as compared with
that (9.5 h) of the unsubstituted instance (1g) (Table 1/Entries 8–10). In these cases again, the k2 rate
constants (0.61, 0.42, and 0.31, respectively) determined the overall reactivity.
To study the effect of substituents on the rate of the hydrolysis further, three additional model
compounds, diethyl benzylphosphonate (4k), diethyl
-phenylethylphosphonate (4m) were also subjected to hydrolysis, under the conditions applied for
the -hydroxybenzylphosphonates (1a ) above (Scheme 2, Table 2, Figure 3 and Figures S9 and S10
in Supplementary Materials). It was found that the hydrolysis of the benzylphosphonate (4k) took
longer than that of the -hydroxy derivative 1g (15 h versus 9.5 h, Table 2/Entry 1 and Table 1/Entry 7).
α-phenylethylphosphonate (4l), and diethyl
β
α
–j
α
The k1 constant was somewhat larger for the hydrolysis of species 4k than that for 1g, but the decisive
k2 value become lower, as demonstrated by 1.12 h−1 and 0.20 h−1 versus 1.03 h−1 and 0.35 h−1 data
pairs, respectively. Placing a Me group instead of the OH function on the
-phenylethylphosphonate 4l, the hydrolysis became even slower, and it was complete only after 25 h.
The smallest k values (k1 = 0.51 h−1, k2 = 0.11 h−1) were obtained in this case (Table 2/Entry 2). It is
obvious that the lack of the electron-withdrawing OH group in position , or the appearance of an
α C atom, i.e., starting from
α
α

Molecules 2020, 25, 3793
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Me group instead of the HO function decreases the electrophilicity of the P atom of the P=O-function.
The hydrolysis of
-phenylethylphosphonate (4m) with a reaction time of 20 h and k values of 0.70 h−1
and 0.15 h−1 (Table 2/Entry 3) occupied an intermediate position.
β
O
O
O
H2O /cc.HCl
H2O/ cc.HCl
Y
P OEt
OEt
4
Y
P OEt
OH
Y
P OH
OH
k1
k2
5
6
Scheme 2. The two-step hydrolysis of other phosphonate derivatives. For the Y substituents see
Table 2.
Table 2. Experimental and kinetic data on the two-step hydrolysis of phosphonates 4k–m.
k1 (h−1
)
k2 (h−1
)
Entry
Y
tmax (h)
tr (h)
R2
1
2
PhCH2 (k)
PhCHMe (l)
Ph(CH2)2
(m)
2
4
15
25
1.12
0.51
0.20
0.11
0.983
0.940
3
2.75
20
0.70
0.15
0.949
Figure 3. Concentration profile for the components during the hydrolysis of diethyl benzylphosphonate
(4k) under optimum conditions. The R2 measure of goodness of fit is 0.983.
It is noted that the hydrolyses of the phosphonate function take place via the SN2 mechanism,
i.e., by the nucleophilic attack of the water molecule on the P=O function. In the consecutive series,
the fission of the second P-O-C bond is the rate-determining step.
The overall order of reactivity of the phosphonates (1a–j and 4k–m) observed under acidic
conditions was summarized in Table 3.
Table 3. Reactivity order of the phosphonates 1a–j and 4k–m in acidic hydrolyses characterized by tr,
as well as k1 and k2.
tr (h)
k1 (h−1
k2 (h−1
2.5–6.0
3.36–5.18
0.67–1.24
6.5
2.64
0.60
5.5–9.0
1.08–1.40
0.31–0.61
8
1.64
0.31
9.5
1.03
0.35
15
1.12
0.20
20
0.70
0.15
25
0.51
0.11
)
)

Molecules 2020, 25, 3793
5 of 10
3. Materials and Methods
3.1. General Information
The 31P, 13C, and 1H NMR spectra were taken on a Bruker DRX-500 spectrometer operating at
202.4, 125.7, and 500 MHz, respectively. The couplings are given in Hz. LC-MS measurements were
performed with an Agilent 1200 liquid chromatography system coupled with a 6130 quadrupole
mass spectrometer equipped with an ESI ion source (Agilent Technologies, Palo Alto, CA, USA).
High-resolution mass spectrometric measurements were performed using a Thermo Velos Pro Orbitrap
Elite hybrid mass spectrometer in positive electrospray mode.
3.2. Use of the 31P NMR Spectra in Quantitative Analysis
The composition of the reaction mixture was determined by the integration of the areas under the
corresponding peaks of the starting material, intermediate, and product in the 31P NMR spectra.
3.3. Curve Fitting on the Time–Relative Quantity Data Pairs
The acidic hydrolysis was modeled assuming pseudo-first-order kinetics. The concentration
of water and hydrochloric acid was constant during the reaction, and their initial concentration
is incorporated in the pseudo-first-order rate constants k1 and k2. The corresponding differential
equations used in the model are the following:
d[diester]
= −k1[diester]
(1)
dt
d[ester − acid]
= k1[diester] − k2[ester − acid]
(2)
(3)
dt
d[acid]
= k2[ester − acid]
dt
where [diester], [ester-acid], and [acid] are the time-dependent molarities of the dialkyl
α-
hydroxyphosphonate, the phosphonic ester–acid intermediate, and the phosphonic acid, respectively,
and k1 and k2 are the pseudo-first-order rate constants of the first and the second step of the hydrolysis.
The solution of the differential equations is the following (k1 , k2):
[diester] = c0e−k t
(4)
(5)
1
!
k1
k2 − k1
k1
k2 − k1
[ester − acid] = c0
e−k t
−
e−k t
1
2
!
k2
k2 − k1
k1
k2 − k1
e−k t
+
e−k t = c0 − [diester] − [ester − acid]
(6)
1
2
[acid] = c0 1 −
where c0 is the initial molarity of the dialkyl α-hydroxyphosphonate.
The relative quantity of the components is their molarity divided by the sum of the three molarities
(which is c0). The calculated time–composition curves are described by the following equations,
by leaving the k1 and k2 rate constants as parameters:
diestercalcd = e−k t × 100%
(7)
1
ꢀ
ꢁ
k1
k2 − k1
e−k t − e−k t × 100%
(8)
(9)
1
2
ester − acidcalcd
=
acidcalcd = 100% − diestercalcd − ester − acidcalcd
.

Molecules 2020, 25, 3793
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During the calculation of the rate constants, we first gave arbitrary initial values to k1 and k2, then,
we optimized their values such that the sum of the squares of the differences between the experimental
and calculated compositions became minimal:
ꢀ
ꢁ
n
P
2
SSres
=
+
+
diesterexp,i − diestercalcd,i
i=1
ꢀ
ꢁ
n
P
2
ester − acidexp,i − ester − acidcalcd,i
(10)
i=1
ꢀ
ꢁ
n
P
2
acidexp,i − acidcalcd,i → min
i=1
where n is the number of experimental time–composition data points measured at reaction times t1, t2,
. . . , tn.
The resulting k1 and k2 rate constants and the associated time–composition curves were considered
as the best fits. The best fits were found iteratively, using the nonlinear generalized reduced gradient
method [19] of Microsoft Excel Solver.
ꢀ
ꢁ
SSres
SStot
The R2 measure of goodness of fit is calculated as R2 =
1
−
, where SSres is described
above and
ꢀ
ꢁ
P
P
2
n
n
1
SStot
=
+
+
diesterexp,j
−
i=1 diesterexp,i
j=1
n
ꢀ
ꢁ
P
P
2
n
i=1
n
n
1
(11)
ester − acidexp,j
−
i=1 ester − acidexp,i
n
ꢀ
ꢁ
P
P
2
n
1
acidexp,j
−
i=1 acidexp,j
j=1
n
The reaction time (tmax) corresponding to the maximal ratio of the phosphonic ester–acid
intermediate in the reaction mixture was found as follows:
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
!
ꢂ
ꢀ
ꢁ
d[ester − acidcalcd]ꢂ
d
k1
e−k t − e−k t × 100%
(12)
(13)
ꢂ
1
2
0 =
=
ꢂ
ꢂ
ꢂ
ꢂ
dt
dt k2 − k1
tmax
tmax
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢀ
ꢁ
d
dt
e−k t − e−k t
= −k1e−k tmax + k2e
−k2tmax
1
2
1
0 =
tmax
k1e−k t = k2e−k t
(14)
(15)
max
max
2
1
k1
k2
e−k t
max
2
≡ e(k −k )t
max
1
2
=
e−k t
max
1
ꢀ
ꢁ
k1
k2
ln
tmax
=
.
(16)
k1 − k2
3.4. General Procedure for the Hydrolysis of Phosphonates (1a–j, 4k–m)
A mixture of 3.8 mmol of phosphonate (1a: 0.82 g, 1b: 0.99 g, 1c: 0.95 g, 1d: 0.89 g, 1e: 1.1 g, 1f
:
0.87 g, 1g: 0.93 g, 1h: 1.1 g, 1i: 1.1 g, 1j: 1.0 g, 4k: 0.87 g, 4l: 0.92 g, 4m: 0.92 g), 1.0 mL (6.0 mmol) of
cc. hydrochloric acid, and 2.0 mL of water was stirred at reflux for 2.5–25 h. The concentration of an
aliquot part of the reaction mixture, or the whole mixture, afforded an oil that was analyzed by 31
P
NMR spectroscopy and LC-MS. Identification of the starting materials (1a
2a 5k ), and products (3A 6K
) can be found in Table 4. The 13C and 1H NMR spectral data
of the new intermediates (2a ) were obtained from the spectra of the corresponding mixtures
containing also the phosphonic acids (3A–F).
–j, 4k–m), intermediates
(
–
j,
–m
–
F,
–M
–f, h–j

Molecules 2020, 25, 3793
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Table 4. Identification of the starting phosphonates (1a
–j
,
4k
–m), ester–acid intermediates (2a–j, 5k–m),
and phosphonic acids (3A–F, 6K–M).
δ
31P NMR
Literature
[M + H]
Found (DMSO)
1a
1b
1c
23.9
22.7
23.5
23.8
23.1
24.1
21.8
20.4
21.2
21.7
26.7
29.8
30.6
20.8
18.8
20.3
20.4
19.6
20.8
19.6
18.1
19.0
19.5
23.7
27.0
27.5
18.9
16.6
17.9
18.2
17.4
18.6
21.8
25.7
26.0
23.9 (CDCl3) [20]
21.9 (CDCl3) [20]
22.1 (CDCl3) [20]
23.3 (CDCl3) [21]
–
24.0 (CDCl3) [20]
21.5 (CDCl3) [20]
19.9 (CDCl3) [20]
21.9 (CDCl3) [20]
21.7 (CDCl3) [23]
26.4 (CDCl3) [24]
30.4 (CDCl3) [25]
30.8 (CDCl3) [24]
19.9 (D2O) [26]
216.9
262.2
273.0
235.0
285.1
231
245.1
290.1
354.1
262.1
229.2
243.1
243.1
1d
1e [22] a
1f
1g
1h
1i
1j
4k
4l
4m
2a
203.04675 (203.04677 c)
248.03164 (248.03185 c)
2b b
2c b
2d b
2e b
2f b
2g [27] a
2h b
2i b
2j b
5k
237.00752 (237.00780 c)
221.03692 (221.03735 c)
271.03384 (271.03416 c)
217.06177 (217.06242 c)
217.06193 (217.06242 c)
262.04707 (262.04750 c)
251.02306 (251.02345 c)
235.05267 (235.05300 c)
25.5 (CD3OD) [28]
32.3 (CDCl3) [29]
–
19.4(D2O) [18]
16.4 (D2O) [18]
18.6 (D2O) [18]
18.5 [31]
201.1
215.1
215.1
189.1
234.0
223.0
207.0
257.0
203.1
173.0
187.0
187.0
5l
5m [30] a
3A
3B
3C
3D
3E b
3F
18.8 (D2O) [18]
22.1 (DMSO) [32]
27.8 (CD3OD) [33]
26.7 (DMSO) [34]
6K
6L
6M
a 13C and 1H NMR characterization is available in the literature; b Spectral data are given below; c Calculated value.
13C and 1H NMR characterization of the new ester acids:
δ
Methyl hydrogen 1-(4-nitrophenyl)-1-hydroxymethylphosphonate (2b). 13C NMR (DMSO-d6) : 52.6 (d, 2J =
6.5, OCH3), 69.1 (d, 1J = 157.5, PCH), 122.7 (d, 4J = 2.4, C3), 128.1 (d, 3J = 5.0, C2), 146.5 (d, 5J = 3.3, C4),
147.6 (C1); 1H NMR (DMSO d6) : 3.58 (d, 3J = 10.4, 3H, OMe), 5.05 (d, 2J = 15.5, 1H, PCH), 7.64–7.73
(m, 2H, H2), 8.17–8.23 (m, 2H, H3).
Methyl hydrogen 1-(4-chlorophenyl)-1-hydroxymethylphosphonate (2c). 13C NMR (DMSO-d6)
δ
δ
: 53.0 (d,
2J = 6.5, OCH3), 69.4 (d, 1J = 160.3, PCH), 128.1 (d, 4J = 2.2, C3), 129.5 (d, 3J = 5.3, C2), 132.1 (d, 5J =
3.6, C4), 139.0 (C1); 1H NMR (DMSO-d6)
δ
: 3.55 (d, 3J = 10.3, 3H, OMe), 4.85 (d, 2J = 13.8, 1H, PCH),
7.32–7.47 (m, 4H, Ar).
Methyl hydrogen 1-(4-fluorophenyl)-1-hydroxymethylphosphonate (2d). 13C NMR (DMSO-d6)
δ
: 53.0 (d,
2JP,C = 6.5, OCH3), 69.4 (d, 1JP,C = 161.3, PCH), 114.9 (dd, 2JF,C = 21.2, 4JP,C = 1.9, C3), 129.7 (dd, 3JF,C
8.0, 3JP,C = 5.6, C2), 136.1 (d, 4JF,C = 2.6), 161.9 (dd, 1JF,C = 242.5, 5JP,C = 3.0, C4); 1H NMR (DMSO-d6)
=
δ
:
3.54 (d, 3J = 10.2, 3H, OMe), 4.84 (d, 2J = 13.2, 1H, PCH), 7.09–7.19 (m, 2H, H3), 7.38–7.49 (m, 2H, H2).

Molecules 2020, 25, 3793
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Methyl hydrogen 1-(4-trifluoromethylphenyl)-1-hydroxymethylphosphonate (2e). 13C NMR (DMSO-d6)
δ:
53.1 (d, 2JP,C = 6.5, OCH3), 69.7 (d, 1JP,C = 157.9, PCH), 124.7–125.0 (m, C3), 124.9 (q, 1JF,C = 271.1, CF3),
127.3–128.7 (m, C2, C4), 145.0 (C1); 1H NMR (DMSO-d6)
δ
: 3.56 (d, 3J = 10.3, 3H, OMe), 4.96 (d, 2J =
14.6, 1H, PCH), 7.57–7.72 (m, 4H, Ar).
Methyl hydrogen 1-(4-methylphenyl)-1-hydroxymethylphosphonate (2f). 13C NMR (DMSO-d6)
δ
: 21.2
(Ar-CH3), 52.8 (d, 2JP,C = 6.6, OCH3), 70.0 (d, 1JP,C = 160.2, PCH), 127.7 (d, 3J = 5.6, C2), 128.7 (d, 4J =
2.1, C3), 136.5 (d, 5J = 3.1, C4), 136.9 (C1); 1H NMR (DMSO-d6)
δ
: 2.28 (s, 3H, Ar-CH3), 3.52 (d, 3J = 10.2,
3H, OMe), 4.76 (d, 2J = 13.0, 1H, PCH), 7.06–7.38 (m, 4H, Ar).
Ethyl hydrogen 1-(4-nitrophenyl)-1-hydroxymethylphosphonate (2h
5.6, CH3), 62.0 (d, 2J = 6.5, OCH2), 69.1 (d, 1J = 157.5, PCH), 122.7 (d, 4J = 2.4, C3), 128.2 (d, 3J = 4.9, C2),
146.5 (d, 5J = 3.6, C4), 147.6 (C1); 1H NMR (DMSO-d6) : 1.17 (t, 3JH,H = 7.0, 3H, CH3), 3.91 (dq, 3JP,H
8.1, 3JH,H = 7.0, 2H, OCH2), 5.03 (d, 2J = 15.7, 1H, PCH), 7.65–7.72 (m, 2H, H2), 8.16–8.23 (m, 2H, H3).
Ethyl hydrogen 1-(4-chlorophenyl)-1-hydroxymethylphosphonate (2i). 13C NMR (DMSO-d6) : 16.6 (d, 3J =
5.5, CH3), 61.7 (d, 2J = 6.5, OCH2), 69.3 (d, 1J = 160.7, PCH), 127.7 (d, 4J = 1.9, C3), 129.2 (d, 3J = 5.3, C2),
131.8 (d, 5J = 3.7, C4), 138.6 (C1); 1H NMR (DMSO-d6) : 1.15 (t, 3JH,H = 7.1, 3H, CH3), 3.91 (dq, 3JP,H
7.1, 3JH,H = 7.1, 2H, OCH2), 4.84 (d, 2J = 13.8, 1H, PCH), 7.33–7.47 (m, 4H, Ar).
)
13C NMR (DMSO-d6) : 16.9 (d, 3J =
δ
δ
=
δ
δ
=
Ethyl hydrogen 1-(4-fluorophenyl)-1-hydroxymethylphosphonate (2j). 13C NMR (DMSO-d6) δ: 16.9 (d, 3J =
5.6, CH3), 61.9 (d, 2J = 6.5, OCH2), 69.5 (d, 1JP,C = 161.7, PCH), 114.8 (dd, 2JF,C = 21.1, 4JP,C = 2.0, C3),
129.7 (dd, 3JF,C = 8.2, 3JP,C = 5.5, C2), 136.1 (d, 4JF,C = 2.8), 161.9 (dd, 1JF,C = 242.4, 5JP,C = 3.2, C4); 1H
NMR (DMSO-d6) δ
: 1.15 (t, 3JH,H = 7.0, 3H, CH3), 3.87–3.95 (m, 2H, OCH2), 4.82 (d, 2J = 13.3, 1H, PCH),
7.11–7.17 (m, 2H, H3), 7.42–7.47 (m, 2H, H2).
1-(4-Trifluoromethylphenyl)-1-hydroxymethylphosphonic acid (3e). 13C NMR (DMSO-d6) : 70.5 (d, 1JP,C
δ =
157.7, PCH), 124.7–125.0 (m, C3), 124.9 (q, 1JF,C = 272.3, CF3), 127.2–128.6 (m, C4), 128.4 (d, 3JP,C = 5.0,
C2), 145.6 (C1); 1H NMR (DMSO-d6) δ: 4.80 (d, 2J = 15.0, 1H, PCH), 7.55–7.72 (m, 4H, Ar).
4. Conclusions
Kinetic study of the two-step acidic hydrolysis of a series of dialkyl α-hydroxybenzylphosphonates
and a few related model compounds allowed the mapping of the reactivity of the different substrates.
The two-step hydrolyses were characterized by k1 and k2 pseudo-first-order rate constants belonging
to the formation of the corresponding monoester monoacids and the phosphonic acids, respectively.
Electron-withdrawing substituents increased the rate, while electron-releasing ones slowed down the
hydrolyses starting with the nucleophilic attack of the water molecule. It turned out that the fission of
the second P-O-C unit is the rate-determining step. The intermediate ester–acid species were identified
and characterized.
Supplementary Materials: The following are available online: Figure S1: Concentration profile for the
components during the hydrolysis of dimethyl
α-hydroxy-4-nitrobenzylphosphonate (1b) under optimum
conditions. The R2 measure of goodness of fit is 0.989. Figure S2: Concentration profile for the components
during the hydrolysis of dimethyl -hydroxy-4-chlorobenzylphosphonate (1c) under optimum conditions.
The R2 measure of goodness of fit is 0.987. Figure S3: Concentration profile for the components
during the hydrolysis of dimethyl -hydroxy-4-fluorobenzylphosphonate (1d) under optimum conditions.
The R2 measure of goodness of fit is 0.965. Figure S4: Concentration profile for the components during
the hydrolysis of dimethyl -hydroxy-4-trifluoromethylbenzylphosphonate (1e) under optimum conditions.
The R2 measure of goodness of fit is 0.988. Figure S5: Concentration profile for the components during
the hydrolysis of dimethyl
-hydroxy-4-methylbenzylphosphonate (1f) under optimum conditions. The R2
measure of goodness of fit is 0.962. Figure S6: Concentration profile for the components during the
hydrolysis of diethyl
-hydroxy-4-nitrobenzylphosphonate (1h) under optimum conditions. The R2 measure
of goodness of fit is 0.992. Figure S7: Concentration profile for the components during the hydrolysis of
diethyl
-hydroxy-4-chlorobenzylphosphonate (1i) under optimum conditions. The R2 measure of goodness
of fit is 0.992. Figure S8: Concentration profile for the components during the hydrolysis of diethyl
-hydroxy-4-fluorobenzylphosphonate (1j) under optimum conditions. The R2 measure of goodness of fit is 0.970.
Figure S9: Concentration profile for the components during the hydrolysis of diethyl -phenylethylphosphonate
4l) under optimum conditions. The R2 measure of goodness of fit is 0.940. Figure S10: Concentration profile for the
α
α
α
α
α
α
α
α
(

Molecules 2020, 25, 3793
9 of 10
components during the hydrolysis of diethyl
measure of goodness of fit is 0.949.
β
-phenylethylphosphonate (4m) under optimum conditions. The R2
Author Contributions: Conceptualization, G.K. and Z.R.; methodology, N.H.; software,
Á.S.; formal analysis, N.H.
and J.K.; investigation, N.H.; resources, G.K.; data curation, .S./N.H.; writing—original draft preparation, G.K.
Á
and N.H.; writing—review and editing, G.K.; supervision, G.K.; project administration, G.K.; funding acquisition,
G.K. All authors have read and agreed to the published version of the manuscript.
Funding: This project was funded by the National Research, Development and Innovation Office (K119202
and K134318).
Conflicts of Interest: The authors declare no conflict of interest.
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