Spectroscopic and dynamic NMR study, X-ray crystallography and DFT calculations of two phosphoramidates: (C4H3O 2)P(O)(Cl)C6H14N and (C4H 3O2)P(O)(C6H11NH)2

Article abstract of DOI:10.1016/j.molstruc.2013.04.059

In recent years, research in organophosphorus compounds, particularly phosphoramidates, has attracted attention because of their many applications. In this work, we report a combined experimental and theoretical study on the molecular structure and NMR spectra of two phosphoramidates (furan-2-yl N,N-diisopropylamidochlorophosphate (1) and furan-2-yl N,N,N′,N′- dicyclohexylamidophosphate (2)). In the NMR time scale a free rotation of the CN/PN single bonds was observed at room temperature (298 K) while the rotation freezes below 195 K for compound 1. From dynamic NMR analysis, the activation free energy (ΔG^#) for rotation of the CN/PN bonds was calculated as 9.9 ± 0.3 kcal mol^-1. The experimental data were reinforced by theoretical calculation using the density functional theory method B3LYP and the 6-31G(d) basis set which provided activation energy (ΔE^?) of 9.2 kcal mol^-1. The structures of compounds 1 and 2 were determined by single crystal X-ray diffraction method. Compound 1 is formed by a racemic mixture, whose presence was evidenced only in the structure determination by X-ray.

Full text of DOI:10.1016/j.molstruc.2013.04.059

Accepted Manuscript
Spectroscopic and dynamic NMR study, X-ray crystallography and DFT cal‐
culations of two phosphoramidates: (C4H3O2)P(O)(Cl)C6H14N and
(C4H3O2)P(O)(C6H11NH)2
F.M. Oliveira, L.C.A. Barbosa, A.J. Demuner, Célia R.A. Maltha, S.A.
Fernandes, J.W.de M. Carneiro, R.S. Corrêa, A.C. Doriguetto
PII:
S0022-2860(13)00379-7
DOI:
http://dx.doi.org/10.1016/j.molstruc.2013.04.059
MOLSTR 19714
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Revised Date:
Accepted Date:
27 February 2013
22 April 2013
23 April 2013
Please cite this article as: F.M. Oliveira, L.C.A. Barbosa, A.J. Demuner, C.R.A. Maltha, S.A. Fernandes, J.M.
Carneiro, R.S. Corrêa, A.C. Doriguetto, Spectroscopic and dynamic NMR study, X-ray crystallography and DFT
calculations of two phosphoramidates: (C4H3O2)P(O)(Cl)C6H14N and (C4H3O2)P(O)(C6H11NH)2, Journal of
Molecular Structure (2013), doi: http://dx.doi.org/10.1016/j.molstruc.2013.04.059
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Spectroscopic and dynamic NMR study, X-ray
crystallography and DFT calculations of two
phosphoramidates: (C4H3O2)P(O)(Cl)C6H14N and
(C4H3O2)P(O)(C6H11NH)2
F. M. Oliveiraa, L. C. A. Barbosaa,b*, A. J. Demunera, Célia R. A. Malthaa, S. A.
Fernandesa, J. W. de M. Carneiroc*, R. S. Corrêad and A. C. Doriguettoe
a Chemistry Department, Federal University of Viçosa, CEP 36570-000, Viçosa, MG, Brazil
b Chemistry Department, Federal University of Minas Gerais, CEP 34095-720, Belo Horizonte, MG, Brazil
c Inorganic Chemistry Department, Fluminense Federal University, CEP 24020-141, Niterói, RJ, Brazil
d São Carlos Physics Institute – USP, Cx. postal 369, CEP 13560-970, São Carlos, SP, Brazil
e Institute of Chemistry, Federal University of Alfenas, CEP 37130-000, Alfenas, MG, Brazil
*
Corresponding authors. (L.C.A.B)Tel.: +55 313899 3068; e-mail: lcab@ufmg.br;
(J.W.M.C) Tel.: +55 21 26295114; e-mail: walk@vm.uff.br
Abstract - In recent years, research in organophosphorus compounds, particularly phosphoramidates, has
attracted attention because of their many applications. In this work, we report a combined experimental and
theoretical study on the molecular structure and NMR spectra of two phosphoramidates (furan-2-yl N,N-
diisopropylamidochlorophosphate (1) and furan-2-yl N,N,N′,N′-dicyclohexylamidophosphate (2)). In the
NMR time scale a free rotation of the C-N/P-N single bonds was observed at room temperature (298 K)
while the rotation freezes below 195 K for compound 1. From dynamic NMR analysis, the activation free
energy (G#) for rotation of the C-N/P-N bonds was calculated as 9.9 ± 0.3 kcal mol−1. The experimental
data were reinforced by theoretical calculation using the density functional theory method B3LYP and the
6-31G(d) basis set which provided activation energy (E‡) of 9.2 kcal mol-1. The structures of compounds 1
and 2 were determined by single crystal X-ray diffraction method. Compound 1 is formed by a racemic
mixture, whose presence was evidenced only in the structure determination by X-ray.
Keywords: Phosphoramidate; Crystal structure; Coalescence energy; DFT calculations;
Insecticides, Dynamic NMR.

1. Introduction
Organophosphorus compounds have attracted great attention due to their
biological activities. Among these, one of the most common class are the
phosphoramidates, which are characterized by the presence of at least one –NR1R2 group
(R1 and R2 = alkyl, aryl) in their structures. Phosphoramidates are extensively studied due
to their potential applications as acetylcholinesterase and urease inhibitors [1],
insecticides [2,3], herbicides [4], antifire [5], anticancer drugs [6-8], anti HIV [9-10],
inhibitors of hepatitis C virus [11-12], antimalarial agents [13], and antirust additives in
lubricating oils [14]. Moreover, novel synthesized phosphoramidate derivatives of
fenoprofen, ketoprofen, ibuprofen, indomethacine and diclofenac possess significantly
higher antiproliferative activities than the corresponding nonsteroidal anti-inflammatory
drugs (NSAID) 3-hydroxypropylamides [15].
Continuing our effort to develop new compounds with insecticidal [2,3] and
phytotoxic activity [16-19], we have synthesized new phosphoramidates and quantified
their activity against the Lepidoptera species that attack important commercial crops [3].
Among
the
synthesized
compounds,
(1) and
only
furan-2-yl
N,N-
diisopropylamidochlorophosphate
furan-2-yl
N,N,N′,N′-
dicyclohexylamidophosphate (2) were obtained as single crystals (Fig. 1).
Insert Figure 1
The biological functions of the phosphoramidates most probably are correlated to
their molecular properties [20-23]. Although the crystal structures of some
phosphoramidates have been reported recently [24-27], only a few details about the
structural and spectral properties of such substances have been described in the literature.
Knowledge of structure and molecular properties are important for the detailed

understanding of their effect on the biological functions and help the rational design of
new compounds [28].
Our aim is to provide valid support to the structural characterization of the
phosphoramidates. Dynamic NMR studies have been extensively used to explore the
kinetics and thermodynamics of stereo dynamic processes [29]. Thus, we report the
1
dynamic H and 13C NMR spectra and use them to estimate the rotational barrier
activation free energy (G‡) for hindered rotation of the C-N and P-N bonds [30] in
phosphoramidate 1. Additionally, the single crystal X-ray diffraction data and quantum
chemical calculations using Density Functional Theory (DFT) are also reported.
2. Experimental
2.1. NMR Studies
1
One dimensional H- and 13C-NMR spectra were acquired either with an
1
MERCURY-300/Varian spectrometer at 300.069 MHz for H (32 k data points, 30o
excitation pulse duration of 2.2 s, spectral width of 6 KHz, acquisition time of 3.3 s and
13
relaxation delay of 10 ms) and at 75.452 MHz for C (32 K data points 45o excitation
pulse duration of 6.5 s, spectral width of 19 KHz, acquisition time of 0.8 s and
relaxation delay of 2.0 s) in 5 mm probes with direct detection, using deuterated
dichloromethane or chloroform as a solvent and TMS as internal standard (δ = 0.00).
2.2 - Single-crystal X-ray diffraction
Crystals of compounds 1 and 2 were obtained by gently warming each compound
in hexane, followed by addition of dichloromethane dropwise until the solid was
completely dissolved. The resulting solution was left undisturbed at room temperature.
After 24 hours, white crystals, suitable for X-ray analyses, were formed. They were
separated, washed with cold hexane, and dried.

Well-shaped single crystals of 1 and 2 were chosen for the X-ray experiment. The
measurements were made at 298 K on an Enraf-Nonius Kappa-CCD difractometer with
graphite monochromated Mo K. Data were collected up to ~50° in 2, with a
redundancy of 4. The final unit cell parameters were based on all reflections. The
temperature was controlled using an Oxford Cryosystem low temperature device. Data
collection was made using the COLLECT software [31]; integration and scaling of the
reflections were performed with the HKL Denzo-Scalepack software system [32]. The
structures were solved and the models refined using the SHELXL-97 software [33]. H
atoms on C atoms were positioned stereochemically and were refined with fixed
individual displacement parameters [Uiso(H) = 1.5Ueq(C) for methyl groups or 1.2Ueq(C)
for aromatic, methine and methylene groups], using the SHELXL riding model with C—
H bond lengths of 0.96, 0.98 and 0.97 Å for methyl, methine and methylene groups,
respectively. The hydrogen atoms bonded to the nitrogen atoms in 2 were found in
successive difference Fourier maps and were refined with free coordinates and Uiso(H) =
1.2Ueq(O). WINGX software was used to analyze and prepare the data for publication.
Molecular graphics were prepared using ORTEP-3 for Windows [34] and Mercury [35].
Crystal data, data collection procedures, structure determination methods and refinement
results are summarized below.
2.3. Computational Details
The geometries of the two phosphoramidates 1 and 2 were first designed in the
SPARTAN´10 software [36]. Using the conformer distribution routine of SPARTAN and
the semi-empirical PM3 method [37] a conformational analysis of both species was
carried out to identify the most stable conformers in each case. Those conformers were
then reoptimized with the B3LYP functional [38,39] and the 6-311++G(2d,p) basis set.
Approximated activation energies for rotation around either the P-N or the C-N bonds
were obtained by a relaxed dihedral scan (by 30º step) around the corresponding bond
using the 6-31G(d) basis set. All the DFT calculations were performed using the
Gaussian 09 program package [40].
3. Results and discussion

In a previous work we have described the preparation of some lactone analogous
to the natural compounds called nostoclides [17]. Lactone 3, used as starting material,
was synthesized previously [2]. The treatment of 3 with POCl3 in the presence of
triethylamine afforded compound 4 (Scheme 1), which was not isolated. Subsequent
reaction of 4 with diisopropylamine (2 eq.) and DMAP (5 mol%) furnished 1 in 14%
yield. Formation of 1 resulted from substitution of one of the chlorine atoms in 4 by the
diisopropylamino group. Treatment of 4 with cyclohexylamine (2 eq.) and DMAP (5
mol%) furnished 2 in 10% yield, with the complete substitution of chlorine atoms in 4 by
the nucleophilic cyclohexylamine [3]. The products were obtained as white crystals and
the structures of compounds 1 and 2 were confirmed by single crystal X-ray diffraction
(Figs. 2 and 6).
Insert Scheme 1
Crystal structure analysis
Crystal data, data collection procedures, structure determination methods and
refinement results are summarized in Table 1. Crystallographic data for the structural
analysis of the compounds discussed here have been deposited at the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, and are
available on request quoting the deposition numbers CCDC 902881 and 902882, for 1
and 2, respectively.
Insert Table 1
Figure 2 shows the R enantiomer of 1. Table 2 gives selected experimental and
calculated bond length and angles. Since 1 is a chiral molecule crystallized in a
centrosymmetric space group, its crystal structure is formed by an equimolar mixture of a
pair of enantiomers (R/S: 50/50) (Fig. 3). The intermolecular geometry of 1 was analyzed
using Mogul [41], a knowledge base of molecular geometry derived from the Cambridge
Structural Database (CSD; Version 5.33 of November 2011, with January 2012 and May
2012 updates) [42]. This analysis shows that all bond lengths and bond angles are in
agreement with the values expected for a good X-ray diffraction structure refinement.
The extended least-squares plane through the furan ring including the exocyclic atom O2

[r.m.s = 0.0024 Å and largest deviation = 0.003(2) Å for O3], shows that this moiety is
planar, as expected.
Insert Table 2
Insert Figure 2
Insert Figure 3
The intermolecular analysis of 1 shows that a non-classical hydrogen bond [C—H
= 0.93 Å, C…O = 3.364(3) Å, H4…O = 2.502(3) Å, C—H…O = 154.26o] involving the
furan and P=O group is the main intermolecular force that contributes to the stabilization
of the crystal packing (Figs. 4 and 5). The individual chains are themselves linked by
VDW interactions forming a racemic double chain along [010]. The furan rings in the
double chains are laid in plane parallel to (101) forming a ribbon along [010] (Figs. 4 and
5). The shortest Cl…Cl separation is 5.581(3) Å, which is slightly longer than the limit
(3.52 Å) to be considered as an intermolecular halogen-halogen interaction involving
chlorine [43].
Insert Figure 4
Insert Figure 5
Figure 6 shows an ORTEP view of 2 with the ring label scheme. The main
geometric parameters are given in Table 1 and some experimental and calculated bond
length and bond angles are given in Table 3. Similarly to compound 1, the molecular
conformation of 2 was also analyzed using the MOGUL software, which revealed a good
X-ray diffraction refinement. The extended least-squares plane through the furan ring
including the exocyclic O2 atom [r.m.s = 0.0206 Å and largest deviation = -0.029(1) Å
for O2] shows that also in this case this moiety is considerably planar. The intermolecular
arrangement of the furan rings in 1 and 2 shows that they are similar, as expected.
However, their orientations are different in relation to the O1=P1-O2 plane in the
phosphorus tetrahedral moiety (Fig. 7). The least-squares plane through the furan ring
and the O1=P1-O2 triad form angles of 73.97(7)o and 53.6(1)o for 1 and 2, respectively.
Moreover, in 1 the P=O bond is oriented anti to the C1—O3 bond, whereas in 2 the
corresponding arrangement is syn (Fig. 7). Both cyclohexyl moieties have chair
conformation with weighted average absolute torsion angles of 54.87(10.52)° and
55.42(12.23)° for rings B and C, respectively (1st is the e.s.d. internal and 2nd is the

external one) [44]. Considering the two possible chair conformations of the
cyclohexylamine ring, the C5—N1 and C11—N2 bonds are both in equatorial
orientation.
Insert Figure 6
Either the N1—H1 or N2—H2b groups act as intermolecular H bond donor to the
O1, giving rise to an infinite one-dimensional chain parallel to the [010] direction (Fig. 8
and Table 4). The linkage takes place through the phosphorous tetrahedron by glide b
(normal to a axis)- and translation-related molecules. The orientation of individual chains
along [010] is shown in the packing illustration of 2 onto the plane ac (Fig 9).
Insert Table 3
Insert Figure 7
Insert Figure 8
Insert Figure 9
Insert Table 4
NMR study
The 1H- and 13C-NMR spectra at 298K evidence couplings over long distances in
both phosphoramidates, 1 and 2. The 1H-NMR spectra of compounds 1 and 2 show three
double double doublets corresponding to H-3, H-4 and H-5 (Fig. 10). The furan hydrogen
couples with neighboring hydrogen atoms and shows a ddd splitting pattern due to its
coupling with phosphorus atom at 4 to 5 bond distance (Fig. 10). The J values at 298 K
are shown in Table 5. The NMR spectrum of compound 2 also shows a multiplet at 
3.03-3.18 for the –CH group coupled with the Hax and Heq. A multiplet integrated for 20
hydrogen atoms at  1.05-1.96 for the hydrogen atoms of cyclohexyl coupled with
neighboring hydrogen atoms was also observed. For the NH signal of compound 2 a two
bond distance coupling with the P atom and a two bond distance coupling with –CH of
2
cyclohexyl were observed. A triplet signal at  2.64 is obtained for NH with JP,NH

1
2JNH,CH  10 Hz, a value similar to that described in the literature [25]. The H NMR
spectrum of 1 displays two doublets at  1.29 and 1.34 integrated for 6 hydrogen atoms
each (2JCH3,CH = 6.9 Hz) for the two types of CH3 groups of the isopropyl moieties due to
the fact that the carbon atom of the CH group in the isopropyl substituent is prochiral.

The methine hydrogen of the isopropyl groups appears as a double septet at  3.63 and
3.69 integrated for 2 hydrogen atoms (3JP, CH = 24.3 Hz) due to its coupling with the
methyl groups and the phosphorus atom. This analysis indicates that the rotational energy
barrier around the C-N and P-N bonds must be low, consistent with the equivalent
chemical shifts shown by the isopropyl moieties on the NMR timescale.
Insert Figure 10
13
The C NMR spectra of compounds 1 and 2 show three doublets ( 89, 111 and
135, respectively) due to carbon atoms C-3, C-4 and C-5 (Fig. 11). The signal
multiplicities are due to carbon coupling with phosphorus atom at a distance of 3-4
bonds. Curiously, lower JP,C were obtained for compound 2 (Table 5) than for compound
1. The quaternary carbon atoms of compounds 1 and 2, C-2 (Fig. 11), are coupled to
phosphorus at  149-152 (2JP,C = 6.5 and 5.1 Hz, respectively). For both compounds
2
couplings at long distances were observed, but JP,CH coupling was not observed for
compound 2. A similar behavior was observed for the phosphoramidates described by
Souza et al. (2006) [45]. The 13C spectrum of compound 1 shows distinct signals for the
diastereotopic methyl carbon atoms which appeared as doublets (3JCH3,P = 2.5 and 1.6 Hz)
3
2
due to JPNC coupling, whereas the methine carbon atom doublet shows larger JPNC
coupling (2JCH,P = 4.9 Hz). The 13C NMR spectrum of compound 2 exhibits three signals
for the ten carbon atoms of the –CH2 cyclohexyl moieties. These results indicate that the
spatial orientations of the aliphatic six-membered rings are the same. A (3JP,CH2) coupling
constant of 5.4 Hz was observed for the splitting of the -CH2 carbon atom with the
phosphorus atom. The spectrum observed in this experiment for compound 1 was found
to correspond to that of a racemic mixture, whose evidence appeared only in structure
determination by X-ray (Fig. 3).
Insert Figure 11
Insert Table 5
An important point in the discussion of the equilibrium geometries of the
phosphoramidates is the activation barrier for rotation around the C-N and P-N bonds.
From the analysis of a molecular model, a 180º rotation around the P-N bond, followed
by a 180º rotation around each C-N bonds, results in the equivalence of the two isopropyl
groups. With this in mind, we carried out a NMR variable temperature study for

compound 1. The results allowed calculation of the higher free energy barrier for
rotation, but would not allow us to know which bond (C-N or P-N) corresponds to the
experimental data. From the temperature of coalescence of the hydrogen lines the first-
order rate constant (kcoalescence) was calculated from the expression kcoalescence = ( +
6J2)1/2/(21/2) where  is the difference in chemical shift between the centers of the two
doublets arising from the methyl hydrogen atoms, and J is the coupling constant. From
the 13C NMR and the coalescence temperature, the rate constant is related to the chemical
shift difference from the expression kcoalescence = ()/(21/2) where  is the difference in
chemical shift. Substituting this value into the Eyring rate equation gives the expression
G‡ = RTln(6.62x1012/kcoalescence) [46]. For comparison, the value of the free energy
barrier was calculated from the coalescence of the resonances and by theoretical methods.
The behavior of 1 was monitored by 1H-NMR techniques at variable
temperatures. From the data, the relevant thermodynamic parameters were calculated. To
examine their behavior, the NMR tube containing compound 1 was placed in the NMR
probe and cold slowly from 298 K to 178 K.
The determination of the exact temperature inside the sample is crucial for the
determination of the thermodynamic parameters. An error of ± 2 °C in the temperature
causes an error in ΔG# of 0.15 to 0.2 kcal mol–1 and this is usually the main source of
errors in the dynamic NMR technique [47]. Therefore, the coalescence temperature was
determined by performing several 1H NMR experiments (Figs. 12 and 13).
Insert Figure 12
Insert Figure 13
For compound 1, two separate doublets appeared in the 1H-NMR spectrum at 298
K for the methyl carbons of the isopropyl groups since they are diastereotopic. In this
condition there is a free rotation of the C-N and P-N single bonds so that the isopropyl
13
groups become equivalent. Also, in the C NMR spectrum of 1 at this temperature, two
signals (Fig. 13: a = c ≠ b = d and Scheme 2) are observed for the methyl carbons of the
isopropyl groups. At low-temperature (< 195K), 1H and 13C NMR spectra of compound 1
show signals for two diastereotopic isopropyl groups. Therefore, four signals are
observed for the methyl carbons (Fig. 13: a ≠ c ≠ b ≠ d and Scheme 2) and two signals for
–CH (Fig. 13: e ≠ f and Scheme 2).

Insert Scheme 2
1
The collected H NMR spectra relevant to the dynamic effect are shown in the
following variable-temperature NMR (Figs. 12 and 13).
The coalescence temperature was eventually observed at TC = 195 K in 1H NMR,
and the higher activation energy (G#) for rotation around the C-N and P-N single bonds
was calculated as 9.9 ± 0.3 kcal mol−1. From this experiment we cannot attribute the
calculated value to G# for rotation of C-N or P-N bonds. So, in order to better
understand this process, a molecular computational analysis was carried out.
Computational analysis
To help rationalize the experimental findings, we carried out a set of calculations
for phosphoramidates 1 and 2. The most stable conformers of 1 and 2 were obtained
using the semi-empirical PM3 method [37] in the Spartan software. The geometry of that
conformations were then reoptimized using the B3LYP/6-311++G(2d,p) approach. Each
optimized geometry was confirmed as a local minimum on the potential energy surface.
Selected parameters of the most stable optimized geometries are compared with the X-ray
diffraction data in Tables 2 and 3, which show that in general the experimental and
computed parameters are in close agreement. The only cases that deserve some attention
are the bond angles O1-P1-O2, C8-N1-C5 in 1 and O2-P1-N2 in 2. The computed values
for the O1–P1–O2 bond angles for compounds 1 and 2 are 115.70 and 116.18(o),
respectively. The corresponding experimental bond angles are 110(4)(o) and 113(2)(o).
For the C8–N1–C5 bond angle in 1 the difference between the experimental and
theoretical values is a bit larger, amounting to 6.9o. For the O2-P1-N2 bond angle in 2 the
corresponding difference is 5.7o.
In addition to the determination of the most stable geometry for each
phosphoramidate we also calculated the approximated activation energy for rotation
around the P-N and C-N single bonds for 1. The goal was to identify whether the
activation parameters determined in the dynamic NMR studies are consistent with
activation energies for rotation around these bonds.
The dynamic process represented in Scheme 2 is enough to interconvert the pairs
of diastereotopic isopropyl groups, however, to completely equilibrate the four methyl

groups (a, b, c and d in Scheme 2) we have also to consider rotation around the C-N
bonds. To determine the activation parameter in each case we performed a set of
calculations with the dihedral angle involving both the P-N and the C-N bonds fixed at a
given value and optimization of the additional degree of freedom. Starting from 0o the
dihedral angle was increased by a 30o step in each case up to the value of 330o. With this,
we could not only confirm the structure of minimal energy but also determine the
transition structure for rotation around the corresponding bond. The B3LYP/6-31G(d)
approach was employed for these calculations.
Rotation around the P-N bond revealed two minima, the global minimum energy
structure, with one of the C-N bonds eclipsing the phosphoryl P=O bond and a local
minimum energy structure with the lone pair on the nitrogen atom eclipsing the P-Cl
bond, 2.1 kcal.mol-1 less stable than the global minimum. The activation energy for
interconversion between these two minima is 6.8 kcal mol-1 (TS1). On the other hand,
rotation around each of the C-N bond also revealed two minima, the global minimum
energy structure and a second one, 3.3 kcal mol-1 above the global minimum. The
activation barrier for rotation around the C-N bond is 9.2 kcal mol-1 (TS2). The last value
closely fits the experimental 9.9±0.3 kcal mol-1 obtained by dynamic NMR studies.
Based on these results we are suggesting that the dynamic behaviour in these
phosphoramidates is characterized by rotation around both the P-N and the C-N bonds,
with activation energy for rotation around the C-N bonds being the higher value.
According to Scheme 2 rotation around the P-N bond interchanges the isopropyl groups
but not the methyl groups within each isopropyl groups. Complete equilibration of the
methyl groups occurs only after rotation around the C-N bond, which is the process with
the higher activation energy.
4. Conclusion
In an effort to prepare new compounds with potential biological activity and
rationalize their molecular properties, two phosphoramidates have been studied by
dynamic NMR, theoretical calculation, spectroscopic data and X-ray crystallography.
Compound 1 is a chiral molecule crystallized in a centrosymmetric space group as an

equimolar mixture of a pair of enantiomers (R/S: 50/50). Geometrical parameters
calculated with DFT methods are consistent with the experimental X-ray data. The
dynamic behavior of 1 was investigated by NMR spectroscopy, which revealed the
activation energy of 9.9 ± 0.3 kcal mol−1. Based on computational calculation of the
activation energies for rotation around the P-N and C-N bonds, this experimental value
was attributed to the C-N bond.
Acknowledgments
We thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq),
Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) and Fundação
Arthur Bernardes (FUNARBE) for financial support and research fellowships (ACF,
AJD, JWMC, ACD, LCAB,SAF and FMO). We thank Prof. Javier Ellena for support
during the single-crystal diffraction measurements.
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Highlights
 In the NMR time scale a rotation of the C-N and P-N single bonds froze at 195
K.
 G# for rotation of the C-N bond of phosphoramidates was calculated by
dynamic NMR
 Compound 1 crystallized in a centresymmetric space group as a mixture of
enantiomers
 Geometrical parameters obtained by DFT are consistent with experimental X-ray
data

Captions for the ilustrations
Scheme1.
Synthesis of phosphoramidates 1 and 2 described by Oliveira and co-workers (2012).
Scheme 2.
Interchangeable processes of compound 1 at 298K.
Fig. 1.
Structure of compounds 1 and 2.
Fig. 2.
The molecular structure of 1 (R enantiomer), showing the atom numbering scheme. Displacement
ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of
arbitrary radii.
Fig. 3.
Molecular fragments highlighting the two enantiomers, a) R (molecule in x, y, z) and b) S (molecule
in -x, -y, -z).
Fig. 4.
A partial packing diagram for 1, showing the racemic double chain formed along [010]. Hydrogen
bonds are shown as dashed lines. [Symmetry codes: (i) x, y-1, z; (ii) x, y+1, z; (iii) -x+1, -y+1,
-z+1; (iv) -x+1, -y+2, -z+1].
Fig. 5.
The crystal packing illustration of 1 onto the plane ac. Hydrogen atoms were omitted for clarity.
Fig. 6.
The molecular structure of 2 with atom and ring labeling. Displacement ellipsoids are drawn at the
30% probability level and H atoms are shown as small spheres of arbitrary radii.
Fig. 7.
Relative orientation of the furan ring and phosphorus tetrahedron in (a) 1 and (b) 2.
Fig. 8.

(a) View of the network of hydrogen bonds parallel to [001] which stabilizes the packing of 2. (b)
View showing only the phosphorous tetrahedral and atom labeling involved in the hydrogen bonds.
Symmetry codes: (i) = -x-1/2, y+1/2, z; (ii) = x, y+1, z; (iii) -x-1/2, y-1/2, z.
Fig. 9.
Packing illustration of 2 onto the plane ac. Hydrogen atoms were omitted for clarity. The colors
represent the eight equivalent positions of Pbac space group.
Fig. 10.
The 1H NMR spectra of compounds 1 and 2 at 298 K in CDCl3.
Fig. 11.
The 13C NMR spectra of the compounds 1 and 2 at 298 K in CDCl3.
Fig. 12.
The variable temperature 1H NMR spectra of 1 from 298 to 178 K in CD2Cl2.
Fig. 13.
The variable temperature 13C NMR spectra of 1 from 298 to 193 K in CD2Cl2.

Fig. 1.
Fig. 2.
Fig. 3.
(a)
(b)

Fig. 4.
Fig. 5.

Fig. 6.
Fig. 7.
(a)
(b)
Fig. 8.
(a)
(b)

Fig. 9.
Fig. 10.
4
3
O
O
Cl
N
2
P
5
O
1
4
3
O
O
NH
2
P
5
HN
O
1

Fig. 11.
4
3
O
O
Cl
N
2
P
5
O
1
4
3
O
O
NH
2
P
5
HN
O
1
Fig. 12.
O
O
Cl
P
N
O

Fig. 13.

Scheme1.
N
H
(2 eq)
O
N
P
O
Cl
O
1
(14%)
O
O
Cl
Cl
DMAP (5 mol%)
Dichloromethane
NH2
POCl3, Et3N
P
O
O
Dichloromethane
O
3
4
O
O
NH
NH
(2 eq)
P
O
2
(10%)
Scheme 2.

Table 1 - Crystal data, data collection details and structure refinement results for 1 and 2.
1
2
Empirical formula
Formula weight
Crystal system
Space Group
C10H17N1O3P1
265.67
Triclinic
P-1
C16H27N2O3P1
326.27
Orthorhombic
Pbca
a=7.4216(2)
b=8.4341(3)
c=11.9649(4)
=87.914(2)
=73.647(2)
=70.935(2)
677.94(4)
2
1.301
0.393
280
0.21 x 0.24 x 0.38
26
-9<=h<=9,
-10<=k<=10,
-14<=l<=14
a=11.8810(5)
b=8.9415(3)
c=32.847(1)
===90o
Unit cell (Å, º)
Volume (Å3)
Z
3489.5(2)
8
1.242
0.171
1408
0.19 x 0.23 x 0.26
25
-13<=h<=14,
-9<=k<=10,
Density (mg/m3)
µ (mm-1)
F (000)
Crystal size (mm3)

max (º)
Index ranges
-19<=l<=40
Reflections collected
9784
16902
Independent reflections
Completeness to max (%)
Data/restraints/parameters
Goodness-of-fit on F2
Final R índices [I>2(I)]
2681 [R(int) = 0.0741]
99.1
2681 / 0 / 149
1.048
R1 = 0.0462, wR2 = 0.1236
R1 = 0.0588, wR2 = 0.1323
3396 [R(int) = 0.0944]
98.6
3396 /0/ 205
0.979
R1 = 0.0477, wR2 = 0.1099
R1 = 0.0981, wR2 = 0.1298
R indices (all data)
max and min (e.Å-3)
0.390 and -0.315 e.Å-3
0.156 and -0.211

Table 2 - Experimental (X-ray) and calculated selected bond lengths [Å] and angles [°] for 1 and MOGUL [41] bond analysis.
Geometric
Parameter
C10–C8
C6–C5
C7–C5
C9–C8
C3–C2
O3–C4
C3–C4
C5–N1
C8–N1
P1–O2
P1–Cl1
O3–C1
C2–C1
O2–C1
P1–N1
Bond length
Mogul average
query
B3LYP/
6-311++G(2d,p)
1.536
Geometric
parameter
C2–C3–C4
O3–C4–C3
C10–C8–N1
C6–C5–N1
C7–C5–N1
C9–C8–N1
C8–N1–C5
O2–P1–O1
C4–O3–C1
O3–C1–C2
C3–C2–C1
P1–N1–C5
P1–N1–C8
O2–P1–N1
O1–P1–N1
Cl1–P1–N1
O2–P1–Cl1
O2–C1–C2
O1–P1–Cl1
Bond angle Mogul average
query
B3LYP/
6-311++G(2d,p)
106.524
110.280
114.579
114.144
112.490
113.037
124.980
115.699
106.292
111.650
105.252
116.189
118.680
106.524
115.699
107.994
95.664
1.516(4)
1.506(4)
1.528(4)
1.512(4)
1.422(4)
1.406(3)
1.292(4)
1.500(3)
1.490(3)
1.605(1)
2.015(1)
1.329(3)
1.311(3)
1.365(3)
1.606(2)
1.452(2)
1.52(3)
1.52(3)
1.52(3)
1.52(3)
1.42(5)
1.38(3)
1.32(4)
1.49(2)
1.49(2)
1.57(1)
2.02(5)
1.35(3)
1.39(4)
1.36(2)
1.62(2)
1.47(3)
108.0(3)
109.7(2)
111.9(2)
111.1(2)
112.0(2)
110.8(2)
117.3(2)
114.95(9)
104.2(2)
113.2(2)
105.0(2)
121.6(2)
119.9(2)
107.0(1)
116.6(1)
109.2(1)
95.12(6)
131.4(2)
111.8()
107(2)
110(2)
113(2)
113(2)
113(2)
113(2)
118(3)
110(4)
107(1)
109(4)
108(1)
121(3)
121(3)
104(5)
114(2)
107(2)
103(2)
132(3)
109(1)
1.529
1.533
1.531
1.434
1.369
1.354
1.501
1.493
1.640
2.071
1.350
1.355
1.358
1.645
1.465
P1–O1
C10–C8–C9
C7–C5–C6
112.7(3)
113.2(3)
112(3)
112(3)
111.194
111.977
132.586
113.175

Table 3 - Experimental (X-ray) and calculated selected bond lengths [Å] and angles [°] for 2 and MOGUL [41] bond analysis.
Geometric
Parameter
C13–C12
C14–C13
C15–C14
C15–C16
C7–C6
C8–C7
C9–C10
C9–C8
C3–C2
O3–C4
C3–C4
C10–C5
C12–C11
C16–C11
C6–C5
C11–N2
C5–N1
Bond length
Mogul average
query
B3LYP/
6-311++G(2d,p)
1.534
Geometric
parameter
C8–C7–C6
C8–C9–C10
C9–C8–C7
C2–C3–C4
O3–C4–C3
C13–C12–C11
C15–C16–C11
C7–C6–C5
C9–C10–C5
C10–C5–C6
C12–C11–C16
C10–C5–N1
C12–C11–N2
C16–C11–N2
C6–C5–N1
P1–N1–C5
P1–N2–C11
O2–P1–O1
C4–O3–C1
O3–C1–C2
C3–C2–C1
O1–P1–N1
O1–P1–N2
O2–P1–N1
O2–P1–N2
N2–P1–N1
O2–C1–C2
Bond
angle
Mogul average
query
B3LYP/
6-311++G(2d,p)
111.787
111.675
111.255
106.842
110.089
111.864
111.747
111.861
111.883
110.945
110.803
111.889
109.983
112.456
110.999
127.827
129.383
116.179
106.196
111.658
105.214
110.529
115.129
104.340
97.831
1.528(3)
1.501(4)
1.513(3)
1.520(3)
1.518(3)
1.498(3)
1.510(3)
1.517(3)
1.424(4)
1.371(3)
1.315(4)
1.505(3)
1.515(3)
1.515(3)
1.505(3)
1.471(3)
1.471(3)
1.461(1)
1.346(2)
1.336(3)
1.353(2)
1.640(1)
1.612(2)
1.601(2)
1.53(3)
1.51(4)
1.51(4)
1.53(3)
1.53(3)
1.51(4)
1.53(3)
1.51(4)
1.42(5)
1.38(3)
1.32(4)
1.51(3)
1.51(3)
1.51(3)
1.51(3)
1.47(2)
1.47(2)
1.48(1)
1.35(3)
1.39(4)
1.36(2)
1.60(1)
1.62(1)
1.62(1)
112.0(2)
111.0(2)
110.7(2)
107.1(2)
110.5(2)
111.4(2)
111.6(2)
111.8(2)
112.0(2)
110.6(2)
110.9(2)
112.6(2)
109.6(2)
112.8(2)
111.0(2)
123.2(1)
123.7(1)
108.3(8)
105.7(2)
111.4(2)
105.3(2)
113.63(9)
117.47(9)
107.47(9)
101.67(9)
107.3(1)
133.4(2)
111(2)
111(3)
111(4)
107(2)
110(2)
111(2)
111(2)
111(2)
111(2)
111(2)
111(2)
111(2)
111(2)
111(2)
111(2)
124(2)
124(2)
113(2)
107(1)
109(4)
108(1)
113(4)
113(4)
103(5)
103(5)
109(2)
131(3)
1.533
1.534
1.534
1.534
1.532
1.534
1.533
1.435
1.374
1.353
1.535
1.536
1.535
1.536
1.464
1.472
1.472
1.355
1.355
1.349
1.651
1.656
1.649
P1–O1
O3–C1
C2–C1
O2–C1
P1–O2
P1–N1
P1–N2
C14 C13 C12
C14 C15 C16
C15 C14 C13
111.1(2)
111.1(2)
111.3(2)
111(2)
111(2)
111(3)
111.750
111.698
111.193
111.768
133.844

Table 4 – Intermolecular hydrogen bond length (Å) and angles (°) for 1. ‘D’ and ‘A’ mean
hydrogen donor and acceptor, respectively.
D-H...A
D-H
H...A
2.44(2)
2.22(3)
D...A
D-H...A
147(2)
162(3)
N1-H1...O1i
N2-H2b…O1i
0.77(3)
0.72(3)
3.110(2)
2.908(2)
Symmetry codes (as Fig. 8: (i) -x-1/2, y+1/2, z