NMR spectroscopic study of some novel N,N-disubstituted phosphonoacetamides

Article abstract of DOI:10.1016/j.molstruc.2008.12.070

The complete ¹H and ¹³C NMR assignments of a series of tertiary phosphonoacetamides (1) with different N-substitution patterns are reported. N,N-Dialkyl derivatives show two sets of signals due to hindered rotation of the (O)C{single bond}N bond, which originate E/Z diastereoisomers for unsymmetrically N,N-disubstituted derivatives. Complete assignment of the ¹H NMR resonances of both rotamers was made on the basis of the magnitude of the diamagnetic shifts (Δδ) experienced by the signals on changing the solvent from CDCl₃ to C₆D₆, and confirmed in the corresponding NOESY spectra. Differential assignment of the ¹³C NMR signals was performed by HSQC experiments. N-Alkyl-N-phenyl phosphonoacetamides show a unique set of signals corresponding to the E isomers as disclosed by NOESY experiments.

Full text of DOI:10.1016/j.molstruc.2008.12.070

Journal of Molecular Structure 921 (2009) 215–218
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Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
NMR spectroscopic study of some novel N,N-disubstituted phosphonoacetamides
*
Liliana R. Orelli , Nadia Gruber
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Junin 956, Piso 3, (1113) Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
The complete 1H and 13C NMR assignments of a series of tertiary phosphonoacetamides (1) with different
N-substitution patterns are reported. N,N-Dialkyl derivatives show two sets of signals due to hindered
rotation of the (O)CAN bond, which originate E/Z diastereoisomers for unsymmetrically N,N-disubsti-
tuted derivatives. Complete assignment of the 1H NMR resonances of both rotamers was made on the
Article history:
Received 5 December 2008
Received in revised form 26 December 2008
Accepted 31 December 2008
Available online 11 January 2009
basis of the magnitude of the diamagnetic shifts (
Dd) experienced by the signals on changing the solvent
from CDCl3 to C6D6, and confirmed in the corresponding NOESY spectra. Differential assignment of the 13
C
Keywords:
NMR
Hindered rotation
Amides
NMR signals was performed by HSQC experiments. N-Alkyl-N-phenyl phosphonoacetamides show a
unique set of signals corresponding to the E isomers as disclosed by NOESY experiments.
Ó 2009 Elsevier B.V. All rights reserved.
Phosphonoacetamides
Phosphorus compounds
1. Introduction
non isolable E/Z diastereomers, which can be observed as two dif-
ferent sets of signals unless the equilibrium is highly biased to-
Structural features of amides have been widely studied by NMR
spectroscopy and molecular modeling methods, as they represent
model compounds for the peptide bond [1]. The planar arrange-
ment of the substituents in amides, due to partial (O)CAN double
bond character, has a strong influence on the superstructure of
peptides and proteins [2], while E/Z isomerization is a key process
involved in protein folding and biocatalysis [3]. NMR spectroscopy
has been widely used for the study of restricted rotation in amides
from early [4] up to recent years [5]. Some very recent reports fo-
wards one of them.
We present here the spectral characterization of a series novel
tertiary phosphonoacetamides with different substitution patterns.
Although all of the compounds evidence hindered rotation around
the (O)CAN bond, different situations arise depending on the nat-
ure of the N-substituents. N,N-Dialkyl derivatives 1a–d display two
sets of signals corresponding to both rotamers. Differential assign-
ment of the 1H signals was performed by means of their monodi-
mensional spectra run in CDCl3 and C6D6, and confirmed by
NOESY. Differential assignment of the 13C NMR signals was per-
formed by HSQC experiments. At variance with compounds 1a–d,
in N-phenyl-N-alkyl derivatives 1e and 1f only one diastereoiso-
mer is detected. For unsymmetrically N,N-disubstituted phospho-
noacetamides 1b–f, the influence of the N-substituents on the E/Z
equilibrium is also analyzed.
cus their interest on acetamides [6] and their a-substituted deriv-
atives [1,7,8]. Phosphonoacetamides are interesting due to their
capability of complexing different metals, and have found applica-
tion in the diagnosis and treatment of several diseases [9], as
extracting agents for alkaline, alkaline earth and transition metals
[10], and as reaction catalysts [11]. In organic synthesis, such com-
pounds represent key synthetic precursors of
a,b-unsaturated
amides [12]. As part of ongoing research on the LiOH promoted
Horner–Wadsworth–Emmons olefination of carbonyl compounds
[13], we recently needed to prepare some N,N-disubstituted phos-
phonoacetamides. To our knowledge, no systematic study on the
spectral features of such compounds is available in the literature.
The partial double bond character of the (O)CAN bond in
amides causes a substantial rotational barrier, which ranges be-
tween 15 and 23 kcal/mol [14,15]. In the NMR spectra, this leads
to nonequivalence of both N-substituents. For unsymmetrically
N-substituted amides, hindered rotation entails the existence of
2. Experimental
2.1. Chemistry
Compounds 1a–f were prepared by reaction of the correspond-
ing chloroacetamides (1 mmole) and triethyl phosphite (2 mmole).
The mixtures were refluxed at 120 C for 12 h. The compounds were
obtained as oils in 64–73% yields. Analytical data of compound 1e
were reported in the literature [16]. Analytical data of new
compounds are as follows. Compound 1a, anal. calcd. for
C10H20NO4P: C, 48.19; H, 8.09; N, 5.62. Found: C, 48.27; H, 8.13;
N, 5.51. Compound 1b, anal. calcd. for C14H22NO4P: C, 56.18; H,
7.41; N, 4.68. Found: C, 56.03; H, 7.46; N, 7.49. Compound 1c, anal.
* Corresponding author. Tel./fax: +54 1 149648250.
E-mail addresses: von_orelli@yahoo.com, lorelli@ffyb.uba.ar (L.R. Orelli).
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2008.12.070

216
L.R. Orelli, N. Gruber / Journal of Molecular Structure 921 (2009) 215–218
calcd. for C15H24NO4P: C, 57.50; H, 7.72; N, 4.47. Found: C, 57.39;
H, 7.81; N, 4.48. Compound 1d, anal. calcd. for C10H20NO4P: C,
58.70; H, 8.01; N, 4.28. Found: C, 58.78; H, 8.09, N, 4.07. Compound
1f, anal. calcd. for C14H22NO4P: C, 56.18; H, 7.41; N, 4.68. Found: C,
56.1; H, 7.51; N, 4.74.
Due to hindered (O)CAN rotation, compound 1a displays sepa-
rate 1H signals for methylenes c–f, both in CDCl3 and C6D6 (Tables 1
and 2). Previous data in the literature [14] indicate that signals of
N-alkyl groups trans to the carbonyl oxygen experience a stronger
diamagnetic shift (Dd) on changing the solvent from CDCl3 to C6D6.
Following this criterion, the triplet in 1a was attributed to the
methylene group trans to the carbonyl oxygen (f), and the double
2.2. Spectra
triplet to the cis methylene (c) (
D
d = ꢀ0.42 and ꢀ0.07 ppm, respec-
1H and 13C NMR spectra were recorded on a Bruker Avance II
500 spectrometer operating at 500.13 and 125.77 MHz, respec-
tively. Spectra were acquired from samples as solutions at room
temperature in 5 mm tubes. Unless otherwise indicated, deutero-
chloroform was used as the solvent. Chemical shifts (d) are re-
ported in ppm, referenced to TMS as an internal standard.
Coupling constants (J) are reported in Hz. Multiplicities are quoted
as singlet (s), doublet (d), double doublet (dd), triplet (t), quartet
(q), heptet (h) and multiplet (m). 1H-detected, one-bond HSQC
spectra were recorded on a Bruker Avance II 500 spectrometer.
Phase-sensitive NOESY spectra were recorded on the same spec-
trometer. Reagents, solvents and starting materials were pur-
chased from standard sources.
tively). The additional splitting of the second signal may arise from
long-range coupling with the 31P nucleus. This tentative assign-
ment was confirmed by the correlations observed in the corre-
sponding NOESY spectrum, which also allowed for the
assignment of methylenes d and e (Fig. 2). The 13C NMR spectrum
of 1a (Table 3) also displays separate signals for both rotamers
around the (O)CAN bond. Unambiguous differential assignment
of the resonances (Table 3) was performed on the basis of the cor-
relations observed in the corresponding HSQC spectrum.
1H spectra of compounds 1b–d also show two sets of signals
with different populations, corresponding to E/Z diastereomers.
Differential assignment of the 1H resonances of both stereoisomers
of 1b–d (Table 1) was performed on the basis of the criterion pre-
viously applied for 1a. Thus, for 1b, singlets at 2.96 and 3.02 ppm
3. Results and discussion
(
D
d = ꢀ0.25 and ꢀ0.48 ppm) were attributed, respectively, to the
cis and trans N-CH3 groups. Singlets at 4.68 and 4.60 ppm were as-
signed, respectively, to the trans and cis benzyl methylenes
The compounds described in this work are shown in Fig. 1. 1H
NMR chemical shifts, multiplicities and relative populations of
E/Z diastereomers of compounds 1a–f (CDCl3) are given in Table
1. 1H NMR chemical shifts, multiplicities and relative populations
of both diastereomers of compounds 1a–d (C6D6) are given in Table
2. 13C NMR chemical shifts of compounds 1a–f (CDCl3) are given in
Table 3. For compounds 1a–d, differential assignment of the 13C
resonances of both rotamers was unambiguously made on the ba-
sis of the correlations observed in their HSQC spectra.
(D
d = ꢀ0.30 and ꢀ0.18 ppm). For compound 1c, the N-ethyl quar-
tets at 3.42 and 3.45 ppm were attributed, respectively, to the trans
and cis methylene groups (
d = ꢀ0.22 and ꢀ0.05 ppm), and sing-
lets at 4.62 and 4.69 ppm (
d = ꢀ0.02 and ꢀ0.11 ppm) to the cis
and trans methylenes in the benzyl moieties. For compound 1d,
the methyne signals at 4.88 and 4.38 ppm d = 0.10 and
D
D
(D
ꢀ0.17 ppm) were assigned, respectively, as cis and trans, while
singlets at 4.66 and 4.57 ppm (
D
d = ꢀ0.06 and ꢀ0.05 ppm) were
Fig. 1. N,N-disubstituted phosphonoacetamides 1a–f.
Table 1
1H NMR signals and relative populations of phosphonoacetamides 1a–f (CDCl3).
Compd.
CH2P
OCH2CH3
R1
R2
Rel. (%)
1a
2.91 (d, J = 22.2)
3.11 (d, J = 22.1)
3.04 (d, J = 22.1)
3.12 (d, J = 22.2)
a: 4.06–4.13 (m), b: 1.26 (m)
a: 4.06–4.21 (m), b: 1.23 (m)
a: 4.06–4.21 (m), b: 1.23 (m)
a: 4.11–4.22 (m), b: 1.33 (m)
c: 3.40 (dt, J1 = 6.9, J2 = 1.9), d: 1.77–1.82 (m), e: 1.86–1.92 (m), f: 3.52 (t, J = 6.8)
–
1b (Z)
1b (E)
1c (Z)
CH2: 4.60 (s), 20–40: 7.21–7.37 (m)
CH2: 4.68 (s), 20–40: 7.21–7.37 (m)
CH2: 4.62 (s), 20–40: 7.17–7.35 (m)
3.02 (s)
2.96 (d, J = 1.3)
63
37
55
CH2:3.42 (q, J = 7.3)*, CH3: 1.16
(t, J = 7.3)
1c (E)
1d (E)
1d (Z)
1e (E)
1f (E)
3.01 (d, J = 22.0)
2.92 (d, J = 22.1)
3.22 (d, J = 22.1)
2.81 (d, J = 21.7)
2.72 (d, J = 21.7)
a: 4.11–4.22 (m), b: 1.33 (m)
a: 4.13–4.18 (m), b: 1.33 (m)
a: 4.19–4.25 (m), b: 1.36 (m)
CH2: 4.69 (s), 20–40: 7.17–7.35 (m)
CH2: 3.45 (q, J = 7.1)*, CH3: 1.13
(t, J = 7.1)
45
´
´
CH2: 4.66 (s), 2–4: 7.25–7.34 (m)
CH: 4.88 (h, J = 6.7), CH3: 1.13
(d, J = 6.7)
CH: 4.38 (h, J = 6.5), CH3: 1.19
(d, J = 6.5)
58
´
´
CH2: 4.57 (s), 2–4: 7.25–7.34 (m)
42
´
´
´
a: 4.08–4.18 (m), b: 1.30
(t, J = 7.0)
a: 4.05–4.11 (m), b: 1.26
(t, J = 7.1)
2: 7.29 (d, J = 7.3), 3: 7.43 (m), 4: 7.35 (m)
3.29 (d, J = 1.2)
100
100
´
´
´
2: 7.20 (d, J = 7.3), 3: 7.39 (t, J = 7.3), 4: 7.32
(t, J = 7.3)
CH2: 3.72 (q, J = 7.2), CH3: 1.08
(t, J = 7.2)
*
Partially overlapping signals.

L.R. Orelli, N. Gruber / Journal of Molecular Structure 921 (2009) 215–218
217
Table 2
1H NMR signals and relative populations of phosphonoacetamides 1a–f (C6D6).
Compd.
CH2P
OCH2CH3
R1
R2
Rel. (%)
1a
2.81 (d, J = 21.8)
2.86 (d, J = 22.1)
2.95 (d, J = 21.8)
3.07 (d, J = 22.0)
3.04 (d, J = 22.0)
2.99 (d, J = 21.8)
3.12 (s) (d, J = 21.8)
g: 4.02–4.16 (m), h: 1.09 (m)*
a: 3.97–4.09 (m), b: 1.05 (m)
a: 3.97–4.09 (m), b: 1.05 (m)
a: 4.08–4.24 (m), b: 1.19 (t, J = 7.1)
a: 4.08–4.24 (m), b: 1.17 (t, J = 7.1)
a: 4.06–4.21 (m), b: 1.12 (dt, J1 = 7.1, J2 = 0.4)
a: 4.06–4.21 (m), b: 1.16 (dt, J1 = 7.1, J2 = 0.4)
c: 3.33 (dt, J1 = 6.7, J2 = 1.8), d,e: 1.13–1.26 (m)*, f: 3.10 (t, J = 6.7)
–
´
´
1b (Z)
1b (E)
1c (Z)
1c (E)
1d (E)
1d (Z)
CH2: 4.42 (s), 2–4: 6.90–7.22 (m)
2.54 (s)
2.71 (d, J = 1.3)
CH2: 3.20 (c, J = 7.2), CH3: 0.78 (t, J = 7.2)
CH2: 3.40 (c, J = 7.1), CH3: 1.07 (t, J = 7.1)
CH: 4.98 (h, J = 6.8), CH3: 1.00 (d, J = 6.8)
CH: 4.21 (h, J = 6.6), CH3: 0.89 (d, J = 6.6)
67
33
55
45
58
42
´
´
CH2: 4.38 (s), 2–4: 6.90–7.22 (m)
´
´
CH2: 4.60 (s), 2–4: 7.08–7.38 (m)
´
´
´
´
´
´
CH2: 4.58 (s), 2–4: 7.08–7.38 (m)
CH2: 4.60 (s), 2–4: 7.05–7.41 (m)
CH2: 4.52 (s), 2–4: 7.05–7.41 (m)
*
Partially overlapping signals.
Table 3
13C NMR signals of phosphonoacetamides 1a–f (CDCl3).
Compd.
CH2P
C@O
OCH2CH3 a b
R1
R2
1a
34.65
(d, J = 133.5)
33.39
(d, J = 131.7)
34.29
(d, J = 131.1)
33.17
(d, J = 134.5)
33.79
(d, J = 133.4)
34.50
(d, J = 132.6)
33.67
(d, J = 132.6)
33.13
163.08
a: 62.50 (d, J = 6.4), b: 16.27
(d, J = 6.4)
a: 62.53 (d, J = 6.8), b: 16.22
(d, J = 6.8)
a: 62.56 (d, J = 5.7), b: 16.22
(d, J = 6.8)
a: 62.58 (d, J = 5.6), b: 16.26
(d, J = 5.6)
a: 62.58(d, J = 5.6), b: 16.26
(d, J = 5.6)
a: 62.51 (d, J = 6.4), b: 16.28
(d, J = 6.4)
a: 62.62 (d, J = 6.4), b: 16.28
(d, J = 6.4)
a: 62.35 (d, J = 6.8), b: 16.26
(d, J = 6.8)
c: 46.03, d: 24.44, e: 25.98, f: 47.54
(d, J = 5.5)
*
164.98*
CH2: 51.00, 1: 136.71, 2–4 : 127.29, 127.77,
30.23
28.81
´
´ ´
1b (Z)
1b (E)
1c (Z)
1c (E)
1d (E)
1d (Z)
1e (E)
1f (E)
(d, J = 5.6)
165.27*
128.48
*
´
´ ´
CH2: 54.13, 1: 136.11, 2–4 : 126.18, 127.60,
(d, 5.6)
128.87:
164.74*
CH2: 47.90, 1: 137.24, 2–4 : 127.20, 127.68,
N-CH2CH3: 42.57, N-CH2CH3:
13.56
N-CH2CH3: 41.48, N-CH2CH3:
12.45
N-CH(CH3)2: 46.16, N-CH(CH3)2:
20.09
N-CH(CH3)2: 50.18, N-CH(CH3)2:
21.31
37.57
*
´
´ ´
(d, J = 5.6)
128.45
165.00*
CH2: 51.42, 1: 136.62 2–4 : 126.23, 127.55,
*
´
´ ´
(d, J = 5.6)
165.78*
128.87
*
´
´ ´
CH2: 46.32, 1: 138.04, 2–4 : 125.71, 127.21,
(d, J = 5.5)
128.80
164.84*
CH2: 43.98, 1: 138.90, 2–4 : 126.54, 126.70,
128.20
*
´
´ ´
(d, J = 5.5)
164.74
(d, J = 5.6)
165.00
´
´ ´
´
1: 143.77, 2,3: 129.81,127.43, 4: 128.10
(d, J = 137.9)
33.50
(d, J = 138.1)
´
´ ´
´
a: 62.38 (d, J = 6.4), b: 16.29
(d, J = 6.4)
1: 142.03, 2,3: 129.77, 128.49, 4: 128.28
N-CH2CH3:44.45, N-CH2CH3:12.84
(d, J = 5.6)
*
Assignment corresponding to both rotamers are exchangeable.
Fig. 2. Relevant correlations observed in the NOESY spectra (CDCl3) of compounds 1a–f.
attributed, respectively, to the trans and cis N-benzyl methylene
groups. In all cases, the remaining signals were attributed to the
major and minor diastereoisomers on the basis of their relative
integration. Assignments of the 1H NMR signals of compounds
1b–d were confirmed by the correlations observed in the corre-
sponding NOESY spectra (Fig. 2). The 13C NMR spectra of com-

218
L.R. Orelli, N. Gruber / Journal of Molecular Structure 921 (2009) 215–218
pounds 1b–d also show separate signals for each diastereoiso-
mer. In each case, differential assignment of the resonances (Table
3) was performed on the basis of the correlations observed in the
corresponding HSQC spectra. For N-benzyl-N-alkyl derivatives
1b–d both diastereoisomers have different populations, showing
approximately the same ratio in CDCl3 and C6D6 (Tables 1 and 2).
From the differential assignments, it can be seen that the Z isomers
(N-benzyl group cis to the carbonyl oxygen) are the predominant
species in the case of 1b and c. According to the relative volumes
of both N-alkyl moieties, the equilibrium is more shifted towards
the Z isomer for the methyl derivative 1b. This preference is re-
versed in N-benzyl-N-isopropyl phosphonoacetamide 1d, in which
the more sterically hindering isopropyl group is cis to the carbonyl
oxygen in the major diastereoisomer (E). In some of the com-
pounds under study, it is noteworthy that the 1H NMR chemical
shifts of the cis and trans methylene groups are reversed with re-
spect to the tendencies previously reported for model compounds
[14], which indicate that cis methylene hydrogens are more
deshielded than their trans counterparts. In fact, in 1a this behav-
iour is reversed, i.e. the cis and trans methylenes appear respec-
tively at 3.40 and 3.52 ppm, while in N-benzyl-N-alkyl phospho-
noacetamides 1b–d the N-CH2Ph signals are more shielded in the
cis than in the trans disposition. As regards the 13C chemical shifts,
in all cases the N-alkyl carbons cis to the carbonyl oxygen are more
shielded than their trans counterparts. For compounds 1b–d, the
CH2P signals cis to the more sterically hindering N-alkyl moieties
are comparatively more deshielded.
model compounds, which was reversed in some cases. The corre-
sponding bidimensional heteronuclear HSQC spectra were used
to assign the 13C NMR signals, by correlating them with the previ-
ously assigned proton resonances.
For compounds 1b–e, the relative stabilities of E/Z diastereo-
mers depend on the relative steric hindrance of both N-substitu-
ents. In N-alkyl-N-phenyl derivatives 1e and 1f, the E/Z
equilibrium is strongly biased towards the E diastereoisomers,
which are the only detectable species. This preference cannot be
entirely attributed to steric effects and may be due, at least in part,
to additional interactions of the N-phenyl group.
Acknowledgements
This work was supported by the University of Buenos Aires (B-
096 grant). We are also grateful to Lic. Ignacio Luppi Berlanga for
technical collaboration.
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We performed the NMR spectroscopic study of a series of ter-
tiary phosphonoacetamides. The compounds under study evidence
hindered rotation around the (O)CAN bond. N,N-Dialkyl deriva-
tives show two sets of signals corresponding to both rotamers,
with different populations for unsymmetrically N-substituted
compounds. In N-phenyl-N-alkyl derivatives, only one diastereo-
isomer is detected. For compounds 1a–d, assignment of the 1H
NMR resonances of both rotamers was based upon the differential
(b) A. Lattanzi, L.R. Orelli, P. Barone, A. Massa, P. Iannece, A. Scettri,
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D
d
experienced by the signals in CDCl3 and C6D6 and confirmed by
NOESY experiments. Differential assignment based on the d crite-
rion was more reliable than the one derived from chemical shifts of
D