Microwave-assisted functionalization of phosphinic acids: Amidations versus esterifications

Article abstract of DOI:10.1002/hc.21068

Both the reaction enthalpies and enthalpies of activation obtained by high-level quantum chemical calculations were against the direct amidation of phosphinic acids under traditional thermal conditions. However, the amidations, not expected to proceed on the basis of the endothermicity and the significantly high enthalpies of activation, did take place under microwave (MW) conditions in 30-36% conversions. As a comparison, the direct esterifications of phosphinic acids that are thermoneutral and have higher enthalpies of activation were quite efficient under MW conditions. The outcome of the MW-assisted amidation is the balance of two effects. The local overheating effect could overcome the barrier meant by the enthalpy of activation, but the endothermicity works against this. Comparison of the results of the syntheses and the energetics calculated for the esterification and amidation of phosphinic acids enabled us to draw more general conclusions on the scope and limitation of the use of MW irradiation in organic syntheses. The traditional amidation of phosphinic acids via the phosphinic chloride intermediate gave the products in much better yields. 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:91-99, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21068

Full text of DOI:10.1002/hc.21068

Heteroatom Chemistry
Volume 24, Number 2, 2013
Microwave-Assisted Functionalization
of Phosphinic Acids: Amidations versus
Esterifications
Gyo¨rgy Keglevich,1 No´ra Zsuzsa Kiss,1 and Tama´s Ko¨rtve´lyesi2
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics 1521, Budapest, Hungary
2Department of Physical Chemistry and Material Science, University of Szeged 6701, Szeged,
Hungary
Received 24 September 2012
View this article online at wileyonlinelibrary.com.
ABSTRACT: Both the reaction enthalpies and en-
DOI 10.1002/hc.21068
thalpies of activation obtained by high-level quantum
chemical calculations were against the direct amida-
tion of phosphinic acids under traditional thermal
conditions. However, the amidations, not expected to
proceed on the basis of the endothermicity and the sig-
nificantly high enthalpies of activation, did take place
under microwave (MW) conditions in 30–36% con-
versions. As a comparison, the direct esterifications
of phosphinic acids that are thermoneutral and have
higher enthalpies of activation were quite efficient un-
der MW conditions. The outcome of the MW-assisted
amidation is the balance of two effects. The local
overheating effect could overcome the barrier meant
by the enthalpy of activation, but the endothermicity
works against this. Comparison of the results of the
syntheses and the energetics calculated for the esteri-
fication and amidation of phosphinic acids enabled
us to draw more general conclusions on the scope
and limitation of the use of MW irradiation in or-
ganic syntheses. The traditional amidation of phos-
INTRODUCTION
Phosphinic acids (1) are known to resist direct esteri-
fication and amidation. For this reason, the phosphi-
nates (3) and phosphinic amides (4) are usually syn-
thesized from the corresponding phosphinic chlo-
rides (2) by reaction with alcohols and amines, re-
spectively (Scheme 1) [1,2].
Although the above procedures are widespread
in laboratories and in industry, they cannot be re-
garded as environmentally friendly (“green”) due to
the hydrochloric acid liberated that has to be re-
moved by a base (or a second molecule of the amine).
There is only one example for the direct esterifica-
tion; in reaction with phenol, the dithio derivative of
phenylphosphinic acid was converted to the corre-
sponding phenylphosphinothioate [3].
phinic acids via the phosphinic chloride intermediate
Realizing the potential of the microwave (MW)
ꢀC
gave the products in much better yields. 2013 Wiley
technique, we attempted the direct esterification
of cyclic phosphinic acids, such as 1-hydroxy-3-
phospholene oxides, 1-hydroxyphospholane oxides,
and a 1-hydroxy-1,2,3,4,5,6-hexahydrophosphinine
oxide. To our surprise, the esterifications took place
in the range of 180–230◦C in sealed tubes. The
outcome depended on the nature of the alcohol
used (Table 1) [4–6]. Obviously, the less volatile the
Periodicals, Inc. Heteroatom Chem 24:91–99, 2013;
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@mail.
bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
Contract grant number: OTKA K83118.
ꢀC
2013 Wiley Periodicals, Inc.
91

92 Keglevich et al.
in most cases, reach 10–50◦C or may be even higher.
The extent of this effect is dependent on the dielectric
constant of the medium. The specific role of MW will
be discussed below, in the context of the reactions
studied.
Encouraged by our previous results, we wished
to study the MW-assisted direct amidation of phos-
phinic acids experimentally and theoretically. It was
also our purpose to compare the MW-promoted es-
terifications and amidations.
SCHEME 1
alcohol is, the higher the reaction temperature may
be that can be attained considering the pressure
limit of 25 bar of the MW equipment. Hence, the
best results (70–95% yields) were obtained with n-
octanol and n-dodecanol as the reaction components
(Table 1, entries 2, 3, 5, 6, 8, and 10). Quantum
chemical calculations suggested that the esterifica-
tion of phosphinic acids is thermoneutral, and the
enthalpy of activation for the rate-determining step
is rather high (102–161 kJ mol−1) [6]. This means
that the phosphinic acids cannot be expected to un-
dergo direct esterification under thermal conditions.
The fact that the esterifications still did take place
on MW irradiation shows the potential of this tech-
nique. The beneficial impact is the consequence of
the so-called local overheating effect [7] that may,
RESULTS AND DISCUSSION
Preparation of 1-Amino-3-phospholene 1-oxides
and 1-Aminophospholane 1-oxides from the
Corresponding Cyclic Phosphinic Acids
We decided to try the direct amidation of 1-
hydroxy-3-methyl-3-phospholene 1-oxide 1 with n-
hexylamine, c-hexylamine, and benzylamine that
are not too volatile (with boiling points in the
range of 132–185◦C) and hence allowing the appli-
cation of a reaction temperature of 220◦C. Work-
ing in a sealed tube and using the amines in a
TABLE 1 Summary of the MW-Assisted Esterification of Phosphinic Acids [5,6]
Entry
R
T (◦C)
p (bar)a
t (h)
Conversion (%)
Yield (%)
Ref.
1
2
3
nBu
C8H17
C12H25
200
220
230
∼14
1.2
0
2
2
2
70 (11)b
100 (12)b
100
58c
71
95
[5]
[6]
[6]
4
5
6
nBu
C8H17
C12H25
220
230
230
∼14
1.5
0
3
2
2
75
100
60
95
95
[5]
[6]
[6]
100 (15)b
7
8
nBu
230
230
∼14
1.5
3
4
58
45d
74d
[5]
[6]
C8H17
100
9
nBu
210
230
∼14
1.5
3
4
65
54e
70e
[5]
[6]
10
C8H17
100
11
nBu
230
∼14
3
61
45d
[5]
aOverpressure.
bThe result of comparative thermal experiment (in parentheses).
c5% 1-hydroxy-3-methyl-2-phospholene 1-oxide was also formed as a by-product.
dAs a mixture of two isomers.
eAs a mixture of three isomers.
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Functionalization of Phosphinic Acids: Amidations versus Esterifications 93
SCHEME 3
Thermodynamic and Kinetic Background of the
Amidation of Phosphinic Acids as Compared to
that of Benzoic Acid
n
SCHEME 2
B3LYP/6-31++G(d,p) calculations were carried out
to evaluate the reaction enthalpy (ꢀH0) and free en-
ergy (ꢀG0) values, as well as the activation param-
15-fold excess, the conversion of hydroxyphosp-
holene oxide 1 to aminophospholene oxides 2a–c
was 30–36% after a 2-h reaction time (Scheme 2).
Prolonged reaction times and the use of catalysts
(e.g., BF3·OEt2) did not promote higher conversions.
Isolated yields of products 2a–c were 25–29%. In
comparative thermal experiments, not even traces of
1-amino-3-phospholene oxides (2a–c) were formed.
Hence, despite the low conversions, the formation
of phosphinic amides 2 under MW conditions is of
principal importance, as it underlines the strength
of MW irradiation. It is, however, noteworthy that
the extent of the MW effect is by far lower in amida-
tions than in esterifications. The energetics associ-
ated with the esterifications and amidations will be
discussed below.
To achieve quantitative conversions, the tra-
ditional methodology had to be followed [8]. Ac-
cording to this, hydroxyphospholene oxide (1)
was first converted to the corresponding phos-
phinic chloride (3), whose reaction with the
amines provided aminophospholene oxides 2a–c
in ca. 81% yield after column chromatography
(Scheme 2). Products 2a–c were characterized by
31P, 13C, and 1H NMR, as well as mass spectral
data.
eters (activation enthalpy [ꢀH#] and activation free
energy [ꢀG#]) for the amidation of phosphinic acids
with primary amines (benzylamine, n-hexylamine,
c-hexylamine, and phenylethylamine) at 210◦C in the
gas phase (Table 2). For comparison purposes, the
amidation of benzoic acid with primary amines was
also calculated. The ca. 7 bar pressure may have only
a slight impact on the energetics; for this, it was ne-
glected in our case. The gas phase calculations mean
a further simplification, but the results so obtained
are informative for the solution phase as well. In
overall, the energetics obtained in the gas phase at
210◦C and 1 bar may provide an adequate basis to
explain our preparative experiences.
For the amidation of benzoic acid, the ꢀG0
and ꢀH0 values fall in the range of –7.5 to –5.9
and –8.2 to –6.7 kJ mol−1, respectively. The mod-
est enthalpy gain justifies the amidations of ben-
zoic acid studied. At the same time, for the ami-
dation of phosphinic acids, such as phenylphos-
phinic acid, dimethylphosphinic acid, 1-hydroxy-
3-phospholene 1-oxides, 1-hydroxyphospholane ox-
ide, and a 1,2,3,4,5,6-hexahydrophosphinine 1-oxide
with the amines mentioned above, the ꢀG0 and ꢀH0
values embrace the ranges 23.8–47.2 and 17.1–39.3
kJ mol−1, respectively, suggesting that the amidation
of phosphinic acids is unfavorable energetically due
to the great extent of endothermicity.
1-Hydroxy-3-methyl-
dimethylphospholane 1-oxides
and
1-hydroxy-3,4-
and were
4
5
also subjected to MW-assisted direct amidation
with benzylamine at 220◦C for 2 h. It was found
that the expected amides 6 and 7 were formed in a
conversion of ca. 31% (Scheme 3). Amides 6 and 7,
formed as two and three isomers, respectively, were
obtained in low (ca. 23%) yields and were charac-
terized by 31P NMR, as well as high-resolution mass
spectral data.
In respect of the activation parameters calcu-
lated for the amidation of benzoic acid and for that
of the phosphinic acids, the following can be said.
For the amidation of benzoic acid, ꢀG# values of
143.4–152.2 kJ mol−1 and ꢀH# values of 52.1–64.0
kJ mol−1 were calculated, whereas for the amidation
of phosphinic acids, significantly higher ꢀG# and
ꢀH# values, 154.7–189.2 and 67.7–106.4 kJ mol−1
,
Heteroatom Chemistry DOI 10.1002/hc

94 Keglevich et al.
TABLE 2 Energetics for the Amidation of Phosphinic Acids at 210◦C Obtained by B3LYP/6-31++G(d,p) Calculations
Reaction Energy and Enthalpy
Parameters (kJ mol−1
Activation Energy and Enthalpy
Parameters (kJ mol−1
)
)
Entry
Acid
Amine
ꢀG0
ꢀH0
ꢀG#
ꢀH#
1
2
3
BnNH2
nHexNH2
BnCH2NH2
–5.9
–7.5
–6.3
–6.7
–8.2
–7.9
149.1
143.4
152.2
59.2
52.1
64.0
4
5
6
BnNH2
nHexNH2
BnCH2NH2
35.0
31.9
29.5
22.7
27.0
23.4
156.3
154.7
157.6
68.6
67.7
71.5
PhP(O)(H)OH
Me2P(O)OH
7
8
nHexNH2
BnCH2NH2
42.0
42.5
35.3
38.0
168.9
174.1
92.0
92.8
9
BnNH2
nHexNH2
cHexNH2
BnCH2NH2
47.2
44.7
37.2
41.1
39.3
32.6
34.3
33.2
168.5
166.4
187.4
168.5
86.1
79.4
99.6
83.2
10
11
12
13
14
15
16
BnNH2
nHexNH2
cHexNH2
BnCH2NH2
46.4
43.1
43.1
38.8
33.9
33.0
34.7
33.7
169.9
168.0
179.4
170.1
88.5
86.5
106.4
90.3
17
18
19
20
BnNH2
nHexNH2
cHexNH2
BnCH2NH2
43.5
43.1
45.9
43.1
35.1
33.9
35.9
35.0
174.7
175.1
195.6
179.7
87.8
85.7
95.8
89.9
21
22
23
BnNH2
nHexNH2
BnCH2NH2
43.1
44.6
43.1
35.1
35.7
35.1
176.4
177.2
181.4
87.8
87.8
91.5
24
25
BnNH2
30.3
23.8
21.7
17.1
189.2
188.5
106.1
104.2
nHexNH2
respectively, were obtained (Table 2). The enthalpy
profile for the amidation of benzoic acid and phenyl-
H-phosphinic acid with n-hexylamine is shown in
Fig. 1. On the basis of the data calculated, it can be
said that neither the ꢀH# values nor the endother-
micity would allow the amidation of the phosphinic
acids to take place under thermal conditions. How-
ever, under MW conditions, a conversion of ca. 33%
could be obtained; ca. two-third parts of the start-
ing phosphinic acid remained unchanged. The ben-
eficial effect of MW allowing the reaction to take
place in a modest conversion stems in the statisti-
cally occurring local overheating effect [7] that may
help to overcome the barrier meant by the relatively
high (68–106 kJ mol−1) enthalpy of activation. At
the same time, the endothermicity works against
the positive effect of local overheating and, hence,
the unfavorable thermodynamics prevents complete
conversions.
A significant steric effect was recognized in
the amidations with c-hexylamine. In these cases
(Table 2, entries 11, 15, and 19), the ꢀH# values were
ca. 10–20 kJ mol−1 higher than for the amidations
with n-hexylamine.
Our calculations showed that in the amidation of
carboxylic acids and phosphinic acids, a four-center
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Functionalization of Phosphinic Acids: Amidations versus Esterifications 95
H
H
H
H
H
R
FIGURE 1 Enthalpy profile for the amidation of benzoic acid and phenyl-H-phosphinic acid with n-hexylamine.
transition state (TS) would be formed, shown as 8
and 9 in a general form.
The activation enthalpies must be the sum of the
activation enthalpies of the H-atom transfer and the
ring strain of the four-membered ring in the transi-
tion state. The situation is similar to that calculated
for the direct esterification of carboxylic acids and
phosphinic acids [6]. The TSs 8 and 9 are derived
from the attack of the amine on the protonated form
of benzoic acid and phosphinic acids. The proto-
nated species are formed by autoprotonation. Calcu-
lations showed that the unprotonated acids did not
undergo the reaction with amines. No stable adduct
may be formed from the interaction of neutral
reactants.
The TSs calculated for the reaction of ben-
zoic acid with n-hexylamine and for the reac-
tions of 1-hydroxy-3-methyl-3-phospholene 1-oxide
1 with n-hexylamine and c-hexylamine, as well as for
the amidation of 1-hydroxy-3-methylphospholane
FIGURE 2 Perspective view for the TS of the amidation of
benzoic acid with n-hexylamine obtained by the B3LYP/6-
31++G(d,p) calculation in the gas phase. Selected geome-
tries (bond distances, bond angles and torsion angles) are
˚
given in A and deg. C–C(1) 1.502, C–NH 1.482, C–O(1)H
1.608, C–O(2)H 1.351, O(1)···H 1.154, NH···H 1.412, NH–
C(2) 1.499, C–C(1)–O(1)H 108.85, C–C(1)–O(2)H 117.16,
C–C(1)–NH 117.71, C(1)–O(1)···H 77.77, C(1)–NH–C(2)
120.61, NH–C(2)–C(3) 114.15, C–C(1)–NH–C(2) –125.89,
C–C(1)–O(1)···H –124.27, C–C(1)–O(2)–H –23.98, C(1)–
NH–C(2)–C(3) 77.86 C(1)–O(1)···H···NH 5.70.
9, the N···H distance is less elongated than in 8. At the
same time, the O···H distance in the TS 8 is shorter
than in 9. According to the bond lengths, the TS is
somewhat looser for the amidation of phosphinic
acid than it is for the amidation of benzoic acid.
It is recalled that the distances for common N–H
1-oxide
4
with benzylamine, are shown in
Figs. 2–5, respectively, together with the geometries
selected.
˚
In the TS for the reaction of benzoic acid with
amines (8), the imaginary frequency is ca. i1400
cm−1 and the bond distances of N···H and O···H
and O–H bonds are 1.03 and 0.99 A, respectively.
For the amidation of benzoic acid, the reaction
and activation entropy values (ꢀS0 and ꢀS#, respec-
tively) fall in the range of –3.5 to –1.7 and –186.4
˚
are ca. 1.41 and 1.16 A, respectively (Table 3). The
to –182.8 J mol−1
K
−1, respectively, whereas for the
imaginary frequencies for the TS of the amidations
of phosphinic acids (9) are ca. i1100–1300 cm−1
,
amidation of phosphinic acids, the ꢀS0 and ꢀS# val-
whereas the bond distances of N···H and O···H are av-
ues were found to be –25.5 to –6.1 and –206.9 to
–151.3 J mol−1
K
−1, respectively. On the basis of
˚
eragely 1.23 and 1.27 A, respectively (Table 3). In TS
Heteroatom Chemistry DOI 10.1002/hc

96 Keglevich et al.
FIGURE 3 Perspective view for the TS of the amidation
of 1-hydroxy-3-methyl-3-phospholene 1-oxide (1) with n-
hexylamine obtained by the B3LYP/6-31++G(d,p) calcula-
tion in the gas phase. Selected geometries (bond distances,
˚
bond angles, and torsion angles) are given in A and deg. P–
O(1) 2.058, P–O(2) 1.664, P–C(1) 1.831, P–C(2) 1.832, O(1)
···H 1.262, NH···H 1.232, P–NH 1.796, NH–C 1.509, C(1)–
P–O(1)H 90.90, C(1)–P–O(2)H 102.46, C(1)–P–NH 125.44,
C(2)–P–O(1)H 86.67, C(2)–P–O(2)H 102.45, C(2)–P–NH
127.06, HN–P–O(1)H 70.99, HN–P–O(2)H 91.10, HO(1)–
P–O(2)H 161.81, P–O(1) ···H···NH –4.01, C(1)–P–O···H –
125.17, C(2)–P–NH···H –72.53, C(1)–P–NH–C –43.92.
FIGURE 5 Perspective view for the TS of the amidation of
1-hydroxy-3,4-dimethylphospholane 1-oxide (5) with benzy-
lamine obtained by the B3LYP/6-31++G(d,p) calculation in
the gas phase. Selected geometries (bond distances, bond
˚
angles, and torsion angles) are given in A and deg. P–C(1)
1.829, P–C(2) 1.839, P–O(1)H 2.091, P–O(2)H 1.660, P–NH
1.800, O(1) ···H 1.279, H···NH 1.219, NH–C) 1.519, C(1)–
P–O(1)H 87.40, C(1)–P–O(2)H 103.43, C(1)–P–NH 123.90,
C(2)–P–O(1)H 88.95, C(2)–P–O(2)H 103.40, C(2)–P–NH
128.08, HN–P–O(1)H 70.71, HN–P–O(2)H 90.70, HO(1)–P–
O(2)H 161.40, O(1) ···H···O(2) 130.00, P–O(1) ···H···NH 1.67,
C(1)–P–O(1) ···H –128.32, C(1)–P–NH–C –167.85.
with κ (transmission coefficient), ꢁ (quantum tun-
neling effect), and l# reaction degeneracy) equal to
1 [9]. The rate constant for the reaction of ben-
zoic acid with benzylamine) is ca. 100 times faster
than it is for the similar amidation of 1-hydroxy-3,4-
dimethylphospholane 1-oxide 5.
In spite of the unfavorable energetics for the ami-
dation of phoshinic acids, the reactions took place
under the effect of MW irradiation, although only
in incomplete conversions. This must be due to the
effect of MW that promotes reactions with higher en-
thalpy of activation [6]. However, the complete con-
versions were prevented by the extent of endother-
micity of the amidations.
FIGURE 4 Perspective view for the TS of the amida-
tion of 1-hydroxy-3-methyl-3-phospholene 1-oxide (1) with c-
hexylamine obtained by the B3LYP/6-31++G(d,p) calculation
in the gas phase. Selected geometries (bond distances, bond
˚
angles, and torsion angles) are given in A and deg. P–C(1)
Comparison of the Energetics of the
Esterification and Amidation of Phosphinic
Acids
1.882, P–C(2) 1.841, P–O(1)H 1.995, P–O(2)H 1.616, P–NH
1.815, O(1) ···H 1.230, NH···H 1.265, C(1)–P–O(1)H 171.66,
C(1)–P–O(2)H 101.12, C(1)–P–NH 100.06, C(2)–P–O(1)H
90.39, C(2)–P–O(2)H 118.75, C(2)–P–NH 118.52, HN–P–
O(1)H 71.60, HN–P–O(2)H 116.63, HO(1)–P–O(2)H 83.20,
P–O(1) ···H···H···NH –7.71, C(1)–P–O(1) ···H 3.86, C(2)–P–
O(1) ···H –115.51, O(2)–P–O(1) ···H 125.57.
It can be seen from Table 4, summarizing the experi-
mental data and from Figure 6 showing the energet-
ics for the comparative derivatization of 1-hydroxy-
3-methyl-3-phospholene 1-oxide, that while the
esterifications of the phosphinic acids are controlled
kinetically, the amidations are governed mainly by
thermodynamic factors. For comparison purposes,
the energetics for the esterification and amidation
of carboxylic acids are also shown in Table 4.
the transition state theory, these data mean that the
preexponential factor is almost the same for the
amidation of benzoic acid and for that of phos-
phinic acids. The rate constant can be calculated
by the Eyring equation κꢁl# kBT/h eꢀS#/R e−ꢀH#/RT
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Functionalization of Phosphinic Acids: Amidations versus Esterifications 97
TABLE 3 Selected Bond Distances in the TS-s for the Amidation of Benzoic Acid and Phosphinic Acids Obtained by B3LYP/6-
31++G(d,p) Calculations
˚
Bond Distances (A)
˚
˚
˚
˚
Entry
Acid
Amine
N···H (A)
O···H (A)
P(C) ···O (A)
P(C) ···N (A)
1
2
BnNH2
1.391
1.412
1.164
1.154
1.626
1.608
1.493
1.482
nHexNH2
3
BnCH2NH2
1.412
1.164
1.620
1.497
Average
1.405
1.160
4
5
6
7
BnNH2
nHexNH2
cHexNH2
BnCH2NH2
1.234
1.232
1.265
1.230
1.261
1.262
1.230
1.265
2.064
2.058
1.995
2.059
1.796
1.796
1.815
1.796
8
9
10
11
BnNH2
nHexNH2
cHexNH2
BnCH2NH2
1.219
1.218
1.262
1.219
1.279
1.279
1.235
1.278
2.091
2.081
1.999
2.078
1.800
1.799
1.816
1.799
12
13
14
BnNH2
nHexNH2
BnCH2NH2
1.219
1.218
1.218
1.279
1.279
1.280
2.091
2.081
2.080
1.800
1.799
1.800
Average (for the amidations of
1.230
1.266
phosphinic acids 1, 4, and 5)
TABLE 4 Summary for the Energetics of the Esterification/Amidation of Carboxylic Acids and Phosphinic Acids in Range (and
as the Middle of the Range)
Esterifications [6]
Amidations
ꢀH0
ꢀG0
ꢀH0
ꢀG#
ꢀH#
ꢀG0
ꢀG#
ꢀH#
RCO2H + RꢁOH −→ RCO2Rꢁ
1–2 (1.5) –4 to –5 (–4.5) 139–158 (148.5)
RCO2H + RꢁNH2 −→ RCONHRꢁ
−H
O
−H
O
2
49–75 (62)
–7.5 to –6 (–7) –8 to –7 (–7.5) 1243–152 (148) 52–64 (58)
6–16 (11)
0.1–4 (2.1)
184–243 (214) 102–161 (132) 24–47 (35.5)
17–39 (28)
155–189 (172) 68–106 (87)
All values are in kJ mol−1
.
One can conclude that the MW irradiation may
be useful in overcoming relatively high enthalpies
of activation, as in the case of the thermoneutral
esterifications of phosphinic acids, but may be only
of partial assistance if the reaction is significantly
endothermic, as in the case of the amidation of phos-
phinic acids.
CONCLUSIONS
In summary, it was found that the thermally
impossible amidation of phosphinic acids took
place with a ca. 33% conversion on MW irra-
diation. B3LYP/6-31++G(d,p) calculations showed
that, in contrast with the amidation of benzoic
acid, that of the phosphinic acids is endothermic,
Heteroatom Chemistry DOI 10.1002/hc

98 Keglevich et al.
H
Ref
H
H
H
H
Rea
FIGURE 6 Enthalpy profile for the esterification and amidation of 1-hydroxy-3-methyl-3-phospholene 1-oxide 1 with butanol
and hexylamine, respectively.
preventing direct amidation under traditional ther-
mal conditions. The relatively high values (68–
106 kJ mol−1) of enthalpy of activation also
preclude the direct amidation. The ca. 33% con-
version achieved on MW irradiation still demon-
strates the potential of the MW technique. The
beneficial impact is the consequence of the local
overheating effect that can overcome enthalpies of
activation with higher values. It is recalled that the
esterifications of phosphinic acids that are practi-
cally thermoneutral and have higher activation en-
thalpies (102–161 kJ mol−1) could be performed ef-
ficiently under MW [6]. The above experiences sug-
gest that the application of MW may be useful in
reactions with higher ꢀH# values. At the same time,
endothermicity may prevent complete conversions.
However, partial conversions may also be of a syn-
thetic value due to the environmentally friendly ac-
complishment. Traditional syntheses of phosphinic
derivatives involve expensive phosphinic chlorides
as the starting materials and the formation of HCl as
the by-product.
General Procedure for the Amidation of
1-Hydroxy-3-methyl-3-phospholene 1-oxide (1)
via the Phosphinic Chloride (3) Intermediate
To 1.50 g (11.4 mmol) of hydroxyphospholene oxide
1 in 5 mL of dry dichloromethane, 1 mL (13.8 mmol)
of thionyl chloride was added and the mixture was
stirred at 26◦C for 24 h. Then the solvent was evap-
orated and the volatile residues were removed in
high vacuum. 1.70 g (∼100%) of 1-chloro-3-methyl-
3-phospholene 1-oxide (3) so obtained was taken up
in 3 mL of dry toluene, and the resulting solution was
added dropwise to a mixture of 11.4 mmol of the pri-
mary amine (n-hexylamine: 1.5 mL, c-hexylamine:
1.4 mL, benzylamine: 1.3 mL) and 1.6 mL (11.4
mmol) of triethylamine in 3 mL of toluene at 60◦C.
The content of the flask was stirred at reflux for 2
h. Then, the amine hydrochloride salt was removed
by filtration and the filtrate was evaporated. The
crude product was purified by column chromatogra-
phy (3% methanol in chloroform, silica gel) to afford
phosphinic amide 2.
1-n-Hexylamino-3-methyl-3-phospholene 1-oxide
(2a). Yield: 82%; 31P NMR (CDCl3) δ: 63.1; 13C NMR
(CDCl3) δ: 13.7 (CH3CH2), 20.4 (3J = 12.1, C3–CH3),
22.3 (CH3CH2), 26.2 (CH2), 31.2 (CH2), 31.8 (3J =
6.2, CH2), 31.9 (1J = 82.0, C5), 34.8 (1J = 85.5, C2),
40.4 (NCH2), 120.5 (2J = 9.6, C4), 136.4 (2J = 15.2,
C3); 1H NMR (CDCl3) δ: 0.85 (t, J = 6.2, 3H, CH3CH2),
1.18–1.35 (m, 6H, 3×CH2), 1.41–1.55 (m, 2H, CH2),
1.76 (s, 3H, C3–CH3), 2.18–2.57 (m, total intensity
5H, 2×PCH2, NH), 2.81–2.96 (m, 2H, NCH2), 5.48
EXPERIMENTAL
General
1
The 31P, 13C, and H 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 hertz. Mass spectrometry was performed on
a ZAB-2SEQ instrument.
The amidations were carried out in a CEM Dis-
cover MW reactor (CEM Microwave Technology
Ltd., Buckingham, UK) equipped with a stirrer and
a pressure controller using 60–160 W irradiation.
(d, J = 33.4, 1H, CH); [M + H]+
= 216.1527,
found
C11H21NOP requires 216.1517.
1-c-Hexylamino-3-methyl-3-phospholene 1-oxide
(2b). Yield: 85%; 31P NMR (CDCl3) δ: 60.7; 13C NMR
Heteroatom Chemistry DOI 10.1002/hc

Microwave-Assisted Functionalization of Phosphinic Acids: Amidations versus Esterifications 99
(CDCl3) δ: 20.5 (3J = 12.1, C3–CH3), 24.9 (C3’), 25.2
the molecules were optimized by the PM6 method
(C4’), 33.1 (1J = 82.2, C5), 36.0 (1J = 85.7, C2), 36.1
(3J = 4.0, C2’), 49.9 (C1’), 120.5 (2J = 9.7, C4), 136.4
(2J = 15.2, C3); 1H NMR (CDCl3) δ: 1.76 (s, C3–CH3),
overlapped by 1.02–2.00 (m, 5 × CH2) total intensity
13H, 2.15–2.60 (m, 5H, NH, 2 × PCH2), 2.94–3.14 (m,
implemented in MOPAC2009 [11]. The preopti-
mized structures were optimized by the B3LYP/6-
31++G(d,p) method. The calculations were per-
formed in the gas phase by Gaussian ‘03 [12]. The
reactant and products had only positive frequencies
in the normal coordinate analysis with the harmonic
oscillator model. The transition states were found by
the QST2 method. One and only one frequency was
found to be imaginary. In the thermochemical cal-
culations, the scale factor was 1.
1H, NH), 5.48 (d, J = 37.1, 1H, CH); [M + H]+
found
= 214.1369, C11H21NOP requires 214.1361.
1-Benzylamino-3-methyl-3-phospholene 1-oxide
(2c). Yield: 76%; 31P NMR (CDCl3) δ: 63.5; 13C NMR
(CDCl3) δ: 20.5 (3J = 12.1, C3–CH3), 32.2 (1J = 81.8,
C5), 35.0 (1J = 85.3, C2), 44.2 (NCH2), 120.6 (2J =
9.8, C4), 127.3 (C2’*, C4’), 128.5 (C3’)*, 136.6 (2J =
15.3, C3), 139.6 (3J = 5.8, C1’), * may be reversed; 1H
NMR (CDCl3) δ: 1.76 (s, 3H, C3–CH3), 2.18–2.62 (m,
4H, 2×PCH2), 3.01–3.16 (m, 1H, NH), 4.08–4.20 (m,
2H, NHCH2), 5.51 (d, J = 33.6, 1H, CH), 7.22–7.38
REFERENCES
[1] Edmundson, R. S. In Comprehensive Organic Chem-
istry; Barton, D.; Ollis D.; Sutherland, I. O. (Eds.);
Pergamon: Oxford, UK, 1979; Vol. 2, Ch. 10.5, p.
1291.
[2] Quin, L.D. A Guide to Organophosphorus Chemistry;
Wiley: New York, 2000.
(m, 5H, Ar); [M + H]+
= 222.1051, C12H17NOP
found
requires 222.1048.
[3] Hopkins, T. R.; Vogel, P. W. J Am Chem Soc 1956,
78, 4447–4450.
[4] Kiss, N. Z.; Luda´nyi, K.; Drahos, L.; Keglevich, G.
Synth Commun 2009, 39, 2392–2404.
[5] Keglevich, G.; Ba´lint, E.; Kiss, N. Z.; Jablonkai, E.;
Hegedu˝s, L.; Gru¨n, A.; Greiner, I. Curr Org Chem
2011, 15, 1802–1810.
General Procedure for the MW-Assisted
Amidation of
1-Hydroxy-3-methyl-3-phospholene 1-oxide 1
and 1-Hydroxyphospholane 1-oxides 4 and 5
A mixture of 0.10 g of the phosphinic acid (1: 0.76
mmol, 4: 0.75 mmol, 5: 0.68 mmol) and 11.3 mmol
of the primary amine (n-hexylamine: 1.5 mL, c-
hexylamine: 1.3 mL, benzylamine: 1.2 mL) was mea-
sured in a sealed tube and irradiated in the MW re-
actor equipped with a pressure controller at 220◦C
for 2 h. (The pressure developed was in the range of
ca. 7 bar) Then, the excess of amine was removed
under reduced pressure and the residue was puri-
fied by flash chromatography. Amides 2a–c, 6, and
7 were formed in conversions of 30–36%, in purities
of 95–97%.
[6] Keglevich, G.; Kiss, N. Z.; Mucsi, Z.; Ko¨rtve´lyesi, T.
Org Biomol Chem 2012, 10, 2011–2018.
[7] Kranjc, K.; Kocˇevar, M. Curr Org Chem 2010, 14,
1050–1074.
´
[8] Keglevich, G.; Kova´cs, A.; To˝ke, L.; Ujsza´szy, K.;
Argay, G.; Czugler, M.; Ka´lma´n, A. Heteroatom Chem
1993, 4, 329–335.
[9] Eyring, H. J Chem Phys 1935, 3, 107–115.
[10] Gilbert, K. E. PCMODEL, Version 7.0; Serena Soft-
ware: Bloomington, IN.
[11] Stewart, J. J. P. J Mol Mod 2007, 13, 1173–1213.
[12] Frisch, M.J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery,
J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone,
V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene,
M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.
E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth,
G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,
O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R.
L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C.
Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.;
Pople, J. A. Gaussian 03, Revision B. 05; Gaussian:
Pittsburgh, PA, 2003.
Phosphinic
Amide
Yield (%) 31P NMR (CDCl3) δ [M + H]+
found
2a
2b
2c
6
26
25
29
24
62.5
60.3
62.9
216.1522
214.1368
222.1053
224.1209
66.1 (50%) and
66.2 (50%)
59.0 (60%), 65.3
(30%), and 64.8
(10%)
7
22
238.1367
Theoretical Calculations
The structures for the reactants, products, and TSs
were built up by PCMODEL [10]. The geometries of
Heteroatom Chemistry DOI 10.1002/hc