The tetrafluoroborate salt of 4-methoxybenzyl N-2-(dimethylamino)ethyl-N- nitrosocarbamate: Synthesis, crystal structure and DFT calculations

Article abstract of DOI:10.1007/s10870-011-9991-z

The tetrafluoroborate salt of 4-methoxybenzyl N-2-(dimethylamino)ethyl-N- nitrosocarbamate was prepared in two steps, via the corresponding carbamate. Its crystal structure is monoclinic, space group P21/c. The unit cell dimensions are: a = 19.499(8) A ,

Full text of DOI:10.1007/s10870-011-9991-z

J Chem Crystallogr (2011) 41:1976–1980
DOI 10.1007/s10870-011-9991-z
ORIGINAL PAPER
The Tetrafluoroborate Salt of 4-Methoxybenzyl
N-2-(dimethylamino)ethyl-N-nitrosocarbamate:
Synthesis, Crystal Structure and DFT Calculations
•
Helene Hedian Vladimir Benin
Received: 24 November 2008 / Accepted: 13 January 2011 / Published online: 28 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The tetrafluoroborate salt of 4-methoxybenzyl
N-2-(dimethylamino)ethyl-N-nitrosocarbamate was prepared
in two steps, via the corresponding carbamate. Its crystal
structure is monoclinic, space group P21/c. The unit cell
light, yielding active intermediates for biological applica-
tions [1]. First reported by Barltrop and Schofield in 1962
[2], photolabile protecting groups have found numerous
applications in biology in the past decade [3, 4]. The pro-
tecting groups (also known as ‘‘caging’’ groups) can render
a bioactive compound inert until they are removed by
photolysis, thus releasing the compound rapidly. Some
examples of commonly used photolabile caging groups
include the o-nitrobenzyl [5], desyl [6] and 2-methoxy-5-
nitrophenyl (MNP) [7]. However, the commonly employed
2-nitrobenzyl photosensitive protecting group has found
limited use in compounds destined for biochemical sys-
tems, due to the release of a toxic by-product: 2-nitro-
benzaldehyde [8, 9].
˚
dimensions are: a = 19.499(8) A, b = 5.877(3) A, c =
˚
˚
15.757(7) A, a = 90°, b = 110.019(7)°, c = 90°, V =
3
1696.5(12) A , Z = 4. The structure exhibits an unexpected,
˚
pseudo-gauche conformation with respect to the C2–C3
bond, due to a stabilizing hydrogen bond between the car-
bonyl oxygen (O1) and the hydrogen atom at the trialky-
lammonium center (H3n), with a distance between them of
˚
2.37 A. DFT calculations on the cation (B3LYP/6-31 ?
G(d)) confirm that the hydrogen bond stabilized gauche
conformation is the global minimum structure.
Zimmerman first demonstrated the efficient photosolv-
olysis of benzyl acetate in 50% aqueous dioxane [10]. His
studies showed that the process occurred in a homolytic
fashion and led to radical-derived products: 4,40-dimeth-
oxybibenzyl and 4-methoxybenzyldioxane. However, a
more recent study of Toscano et al. on the photocleavage of
substituted benzyl diazeniumdiolates demonstrated that the
nature of the cleavage process depended on the pattern of
substitution in the benzylic group [11]. It was found that
compounds with p-donor substituent groups at the 3- and
5-positions of the benzene ring tended to decompose via
heterolytic, rather than homolytic bond cleavage, and
generate resonance stabilized (in the excited state) benzylic
carbocations.
Keywords N-nitrosocarbamate ꢀ Tetrafluoroborate salt ꢀ
Trialkylammonium salt ꢀ Hydrogen bond ꢀ DFT ꢀ
Gauche conformation
Introduction
In recent years considerable effort has been focused on the
development of drugs designed to release their active
species at the desired locality and/or conditions, and also
on identifying structures with photosensitive groups that
would cleave upon irradiation with near UV or visible
Based on the demonstrated potential of substituted ben-
zylic moieties as photolabile protecting groups, we have
recently prepared several classes of substituted benzyl
N-nitrosocarbamates, containing an N-2-(dimethylamino)-
ethyl or an N-2-(methylthio)ethyl group. Our longer term
goal is to develop a new class of anticancer agents, capable of
releasing the active substance photolytically, in controlled
Electronic supplementary material The online version of this
article (doi:10.1007/s10870-011-9991-z) contains supplementary
material, which is available to authorized users.
H. Hedian ꢀ V. Benin (&)
Department of Chemistry, University of Dayton,
300 College Park, Dayton, OH 45469-2357, USA
e-mail: vladimir.benin@notes.udayton.edu
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J Chem Crystallogr (2011) 41:1976–1980
1977
conditions. In the current report we describe the synthesis,
crystal structure and theoretical studies on one interesting
structure: 4-Methoxybenzyl N-2-(dimethylamino)ethyl-N-
nitrosocarbamate, as a tetrafluoroborate salt (Structure 1).
To the best of our knowledge, this is the first reported
structure of an N-nitrosocarbamate salt.
resultant mixture was kept at -15 °C for 15 min, followed
by 3 h at 0 °C. The solvent was removed under reduced
pressure at 0 °C, yielding the product as a yellow solid
(0.70 g, 59% yield). Additional purification was achieved
via recrystallization from acetonitrile at -30 °C, which
yielded the product as pale yellow crystals. Mp 88–90 °C
(dec). 1H NMR (DMSO-d6) d 9.20 (bs, 1H), 7.45
(d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.44 (s,
2H), 4.02 (t, J = 6.3 Hz, 2H), 3.76 (s, 3H), 3.10 (t, J =
6.3 Hz, 2H), 2.76 (s, 6H); 13C NMR (DMSO-d6) d 159.7,
152.9, 130.7, 126.5, 114.0, 69.7, 55.2, 53.0, 42.5, 36.0.
Anal. Calcd. for C13H20BF4N3O4: C, 42.30; H, 5.46; N,
11.38. Found: C, 42.46; H, 5.52; N, 11.25.
O
CH3
N
BF4
CH3
O
N
N
H
O
H3CO
1
Experimental Section
B. Crystal Structure
A. Synthesis
A
crystal (approximate dimensions 0.60 9 0.15 9
1H NMR and 13C NMR spectra of all compounds were
recorded at 300 and 75 MHz, respectively, and referenced
to the solvent (CDCl3: 7.27 and 77.0 ppm; DMSO-d6: 2.49
and 39.5 ppm). Elemental analysis was provided by
Atlantic Microlab, Norcross, GA. 4-Methoxybenzyl phenyl
carbonate was prepared following a literature protocol [12].
Nitrosonium tetrafluoroborate (NOBF4) was purchased
from Fluka. Solvents for synthesis or purification were
used as purchased.
0.05 mm3) was placed onto the tip of a 0.1 mm diameter
glass capillary and mounted on a Bruker SMART Platform
CCD diffractometer for data collection at 173(2) K [13]. A
preliminary set of cell parameters was calculated from
reflections harvested from three sets of 20 frames. These
initial sets of frames were oriented such that orthogonal
wedges of reciprocal space were surveyed. This produced
initial orientation matrices determined from 19 reflections.
The data collection was carried out using MoKa radiation
(graphite monochromator) with a frame time of 90 s and a
detector distance of 4.990 cm. A randomly oriented region
of reciprocal space was surveyed to the extent of one
4-Methoxybenzyl N-2-(dimethylamino)ethylcarbamate
(2)
˚
sphere and to a resolution of 0.84 A. Three major sections
4-Methoxybenzyl phenyl carbonate (1.40 g, 5.42 mmol)
was dissolved in benzene (20 mL). N,N-(dimethyl-
amino)ethylamine (0.43 g, 4.88 mmol, 0.54 mL) was added
and the mixture was refluxed overnight at 80 °C. The
resultant solution was washed with 1 M aq. NaOH
(4 9 25 mL), the organic layer was dried (Na2SO4), and the
solvent removed under reduced pressure. The product was
of frames were collected with 0.308 steps in x at three
different / settings and a detector position of -288 in 2h.
The intensity data were corrected for absorption and decay
(SADABS) [14]. Final cell parameters were calculated
from the xyz centroids of 3136 strong reflections from the
actual data collection after integration (SAINT) [15].
The structure was solved using SHELXS-97 and refined
using SHELXL-97 [16]. The space group P21/c was
determined based on systematic absences and intensity
statistics. A direct-methods solution was calculated which
provided most non-hydrogen atoms from the E-map. Full-
matrix least squares/difference Fourier cycles were per-
formed which located the remaining non-hydrogen atoms.
All non-hydrogen atoms were refined with anisotropic
displacement parameters. The proton on N3 was placed
from the difference map and was refined as a riding atom
with relative isotropic displacement parameters. All
remaining hydrogen atoms were placed in ideal positions
and refined as riding atoms with relative isotropic dis-
placement parameters. The final full matrix least squares
refinement converged to R1 = 0.1123 and wR2 = 0.2490
(F2, all data) (Table 1).
1
collected as 1.03 g of yellow oil (83% yield). H NMR
(CDCl3) d 7.22 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz,
2H), 5.35 (bs, 1H), 4.94 (s, 2H), 3.71 (s, 3H), 3.17 (m, 2H),
2.30 (t, J = 6.0 Hz, 2H), 2.11 (s, 6H); 13C NMR (CDCl3) d
159.5, 156.5, 129.9, 128.8, 113.9, 77.3, 66.4, 58.2, 55.3, 45.1.
Anal. Calcd. for C13H20N2O3: C, 61.88; H, 7.99; N, 11.10.
Found: C, 61.64; H, 8.27; N, 10.95.
4-Methoxybenzyl N-2-(dimethylamino)ethyl-N-
nitrosocarbamate, tetrafluoroborate salt (1)
4-Methoxybenzyl N-2-(dimethylamino)ethylcarbamate (2:
0.78 g, 3.09 mmol) was dissolved in anhydrous acetonitrile
(25 mL) at -15 °C, under nitrogen atmosphere. NOBF4
(0.40 g, 3.42 mmol) was added in one portion, and the
123

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J Chem Crystallogr (2011) 41:1976–1980
(especially anions) the use of diffuse functions is recom-
mended [21–24]. All minima were validated by subsequent
frequency calculations at the same level of theory, and had
sets of only positive second derivatives. Values of free
energy changes were obtained after frequency calculations
and zero-point energy corrections. ZPE corrections were
not scaled.
Table 1 Crystal data and structure refinement
CCDC submission number
Empirical formula
Formula weight
Temperature
704631
13H20BF4N3O4
C
369.13
173(2) K
˚
Wavelength
0.71073 A
Monoclinic
P21/c
Crystal system
Space group
˚
a = 19.499(8) A
Unit cell dimensions
˚
b = 5.877(3) A
Results and Discussion
˚
c = 15.757(7) A
Synthesis
a = 90°
b = 110.019(7)°
c = 90°
The target structure 1 was prepared using a two-step syn-
thetic protocol (Scheme 1). 4-Methoxybenzyl phenyl car-
bonate [12] was reacted with N,N-dimethylethylenediamine
in refluxing benzene, to yield the corresponding carbamate 2.
The latter was nitrosated using NOBF4, in anhydrous ace-
tonitrile. Interestingly, the use of external base (e.g. pyridine)
led to complications and mixtures that were difficult to
resolve. We propose the main reason to be the inherent
competition of the trialkylamine substructure, contained in
2, with any external base, especially amine bases. Thus, a
clean and high yield nitrosation could be conducted only in
the absence of added base. In such conditions the deproto-
nation, necessary to complete the N-nitrosation process, is
accomplished by the second nitrogen center in carbamate 2,
which ends up in the form of a trialkylammonium salt.
3
˚
Volume
1696.5(12) A
Z
4
Density (calculated)
Absorption coefficient
F(000)
1.445 Mg/m3
0.133 mm-1
768
Crystal color, morphology
Crystal size
yellow, needle
0.60 9 0.15 9 0.05 mm3
1.11–25.14°
-22 B h B 23, -6 B k B 6,
-18 B l B 18
12111
Theta range for data collection
Index ranges
Reflections collected
Independent reflections
Observed reflections
2987 [R(int) = 0.0622]
2040
Completeness to theta = 25.14°
Absorption correction
98.6%
Multi-scan
Crystal Structure Analysis
Max. and min. transmission
Refinement method
0.9934 and 0.9245
Full-matrix least-squares on F2
2987/49/265
The structure is the one suggested and an ORTEP drawing
-
is presented in Fig. 1. The BF4 anion was modeled as
Data/restraints/parameters
Goodness-of-fit on F2
1.054
disordered over three positions (67:25:8), and only one
major component is shown in Fig. 1, for greater clarity.
The structure demonstrates the typical planar geometry for
the core N-nitrosocarbamate moiety. The dihedral angles
O1–C1–N1–N2 and C1–N1–N2–O3 have values of 178.5°
and 178.0° correspondingly.
What is interesting about this structure is the unexpected
conformational preference with respect to the C2–C3 bond.
The non-hydrogen groups at both C2 and C3 are sterically
demanding, leading to an anticipated anti conformation,
while in reality the dihedral angle N3–C3–C2–N1 has a
value of 78.3°, much closer to a gauche conformation. The
major factor stabilizing such arrangement seems to be the
close contact and favorable hydrogen bonding interaction
Final R indices [I [ 2sigma(I)]
R indices (all data)
R1 = 0.0784, wR2 = 0.2139
R1 = 0.1123, wR2 = 0.2490
-3
˚
0.761 and -0.709 e A
Largest diff. peak and hole
C. Theoretical Studies
All calculations were performed using the Gaussian03/
GaussView software package [17], on a Linux-operated
QuantumCube QS4-2400C by Parallel Quantum Solutions
(Fayetteville). Calculations were conducted using DFT at
the B3LYP level with the 6-31 ? G(d) basis set [18–20],
taking into account the fact that for charged species
Scheme 1
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J Chem Crystallogr (2011) 41:1976–1980
1979
˚
Table 2 Selected experimental and theoretical bond lengths (A) and
angles (°) for structure 1
Parametera
Experimental value
Theoretical value
O1–C1
1.199(5)
1.310(5)
1.241(5)
1.368(5)
1.398(5)
1.502(6)
178.0(3)
-3.4(5)
10.7(6)
1.237
1.301
1.201
1.413
1.408
1.533
179.6
-3.6
O2–C1
O3–N2
N1–N2
N1–C1
C2–C3
C1–N1–N2–O3
C2–N1–N2–O3
C6–O2–C1–O1
C6–O2–C1–N1
N2–N1–C1–O1
N2–N1–C1–O2
N1–C2–C3–N3
C8–C7–C6–O2
a
3.5
-169.8(3)
-178.4(4)
2.1(5)
-176.6
-165.5
14.7
Fig. 1 ORTEP drawing of the X-ray structure of compound 1.
Thermal ellipsoids are drawn at 50% probability. Hydrogen atoms are
-
given arbitrary radii. Only one component of the disordered BF4
anion is shown
78.3(5)
78.9
-68.8(4)
-87.7
of the hydrogen atom at the ammonium center (H3n) and
˚
the carbonyl oxygen (O1). The distance O1–H3n is 2.37 A
Atom labels in accordance with the crystallographic designation for
compound 1
˚
and the donor–acceptor distance O1–N3 is 2.94 A. These
Theoretical data are for the global minimum structure 1-g-CO, opti-
mized at the B3LYP/6-31 ? G(d) level
distances are longer than the values typical for a hydrogen
˚
bond (typical acceptor–H distance is 1.6–2.0 A, the aver-
˚
age for water is 1.97 A), but are both shorter than the sum
of the van der Waals radii in each case. The interaction
O1–H3n leads to the formation of a seven-membered ring,
with a nonlinear arrangement for the hydrogen bond donor
and acceptor sites (N3–H3n–O1 angle of 125.8°).
Selected experimental bond lengths and angles are
reported in Table 2, together with the theoretical values of
the same parameters, based on the global minimum struc-
ture 1-g-CO as optimized at the B3LYP/6-31 ? G(d) level.
The DFT calculations reproduce fairly accurately the val-
ues of most structural parameters. One notable exception is
the degree of planarity of the N-nitrosocarbamate sub-
structure. It is virtually flat, according to the experimental
structure, while the theoretical result points at about 15°
deviation from planarity. The theoretical and experimental
structures also differ in the conformation at the benzene
ring–benzylic carbon bond (C6–C7 bond). The calculated
structure exhibits a nearly perfect staggered conformation,
with a dihedral angle C8–C7–C6–O2 = -87.7°, while in
the experimental geometry the conformation is close to
eclipsed, with the same dihedral angle having the value of
-68.8°. The hydrogen bond distance H3n–O1 in the cal-
Fig. 2 Crystal packing plot for structure 1. Only one component of
-
the disordered BF4 anion is shown
Theoretical Studies
The stationary point searches were conducted on the cation
solely, in an attempt to analyze its inherent conformational
˚
culated structure is 1.70 A.
-
Crystal packing for structure 1 is shown in Fig. 2. The
individual molecules are arranged back-to-back, with
association realized via interactions of the N-nitrosocar-
bamate substructures with the tetrafluoroborate anions. The
molecules are located in two sets of parallel planes, which
are at an approximate angle of 62°.
preferences, irrespective of interactions with the BF4
anion. Conformational analysis was conducted with respect
to rotations around the C2–C3 and the C3–N3 bonds.
Several minima structures were identified, at the B3LYP/6-
31 ? G(d) level, and they are shown in Fig. 3, together
with their relative Gibbs free energies. The optimized
123

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J Chem Crystallogr (2011) 41:1976–1980
structure acquisition. V. Benin thanks the University of Dayton
Research Council for financial and material support.
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Supplementary Material
Crystallographic data (excluding structure factors) for the
structure reported in this article have been deposited with
the Cambridge crystallographic data centre as supplemen-
tary publication number CCDC 704631. Copies of the data
can be obtained free of charge at http://www.ccdc.cam.
ac.uk/conts/depositing.html, or on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: ?44–
(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk). Cal-
culated energies and thermodynamic parameters of the
conformational minima of compound 1 (cation) are sum-
marized in Table S1.
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Acknowledgments The authors acknowledge Benjamin E. Kucera
and Victor G. Young, Jr., at the X-Ray Crystallographic Laboratory of
the Department of Chemistry, University of Minnesota, for the X-ray
123