Synthesis and crystallographic study of N'-(1-benzylpiperidin-4-yl) acetohydrazide

Article abstract of DOI:10.1007/s10870-010-9771-1

As part of a study into new Fentanyl-derived opioid compounds with potent analgesic activity and reduced side effects the starting material title compound, C₁₄H₂₁N₃O (1), was synthesized and characterized by NMR spectroscopy and single-crystal X-ray diffraction. The crystal structure is monoclinic Cc with unit cell parameters a = 14.1480(3) A, b = 14.1720(4) A, c = 27.6701(7) A, β = 96.956(1)°, α = γ = 90°. The compound has crystallized with four crystallographically unique molecules in the asymmetric unit; each molecule has a very similar conformation and an analysis of the structure shows that although all four unique molecules overlay very well there is no evidence of pseudo-symmetry which would relate the molecules in the higher symmetry space group C2/c. The crystal packing consists of two separate hydrogen bonded chains which are linked together to form a thick 2D structure in the ab plane. Index Abstract: The compound N'-(1-benzylpiperidin-4-yl)acetohydrazide crystallizes with four crystallographically unique molecules in the asymmetric unit; each molecule has a very similar conformation but there is no evidence of pseudo-symmetry.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s10870-010-9771-1

J Chem Crystallogr (2010) 40:961–964
DOI 10.1007/s10870-010-9771-1
ORIGINAL PAPER
Synthesis and Crystallographic Study of N0-(1-benzylpiperidin-4-
yl)acetohydrazide
•
Gary S. Nichol Ruben Vardanyan
•
Victor J. Hruby
Received: 10 November 2009 / Accepted: 10 May 2010 / Published online: 22 May 2010
Ó Springer Science+Business Media, LLC 2010
Abstract As part of a study into new Fentanyl-derived
opioid compounds with potent analgesic activity and
reduced side effects the starting material title compound,
C14H21N3O (1), was synthesized and characterized by NMR
spectroscopy and single-crystal X-ray diffraction. The
crystal structure is monoclinic Cc with unit cell parameters
dependence caused by long term usage [1, 2]. Our research,
therefore, aims to synthesize a range of new analgesics
derived from Fentanyl, with the aim of developing com-
pounds with reduced side effects but which remain potent
analgesics [3–6]. As part of this study the title compound,
1, was synthesized as a starting material for the synthesis of
a wide variety of Fentanyl-based analgesics. We report
here the synthesis and crystal structure determination of 1.
˚
˚
˚
a = 14.1480(3) A, b = 14.1720(4) A, c = 27.6701(7) A,
b = 96.956(1)°, a = c = 90°. The compound has crystal-
lized with four crystallographically unique molecules in the
asymmetric unit; each molecule has a very similar confor-
mation and an analysis of the structure shows that although
all four unique molecules overlay very well there is no evi-
dence of pseudo-symmetry which would relate the mole-
cules in the higher symmetry space group C2/c. The crystal
packing consists of two separate hydrogen bonded chains
which are linked together to form a thick 2D structure in the
ab plane.
Experimental
Synthesis
To a solution of 3.7 g (0.05 mol) of acetylhydrazide in
30 mL of ethanol was added dropwise a solution of 9.45 g
(0.05 mol) of 1-(phenylmethyl)-piperidin-4-one in 30 mL
of ethanol. The mixture was left overnight then the ethanol
was evaporated and the remaining product was crystallized
from acetone giving 11.1 g (90%) of N’-(1-benzylpiper-
idin-4-ylidene)acetohydrazide mp 130–131 °C. EI-MS:m/z
246; HRMS calcd for C14H20N3O: 246.1606; found (ESI,
[M ? H]?): 246.1602 (Scheme 1).
Keywords Organic compounds ꢀ Z0 [ 1 ꢀ
Hydrogen bonding
Introduction
To a solution of 6.125 g (0.025 mol) of N0-(1-benzylpi-
peridin-4-ylidene)acetohydrazide dissolved in a mixture of
25 mL ethanol and 50 mL THF during 15 min was added
by small aliquots 1.9 g (0.05 mol) of NaBH4. The solution
was left overnight then the ethanol and THF were evapo-
rated and to the remaining residue was added 50 mL of
CHCl3 and with cooling and stirring was added dropwise
3 g (0.05 mol) of CH3COOH in 10 mL of water. The
organic layer was separated, dried on MgSO4, and after
evaporation of solvent the residue was recrystallized from
hot ethanol giving 5.25 g (85%) of N0-(1-benzylpiperidin-4-
yl)acetohydrazide, 1, as a crystalline solid, mp 111–112 °C.
We have a long standing research interest in the synthesis
and bioactivity of novel compounds for the treatment of
neuropathic pain. Although morphine is a very potent and
commonly used l opioid, it has serious side effects and
G. S. Nichol (&) ꢀ R. Vardanyan ꢀ V. J. Hruby
Department of Chemistry and Biochemistry,
The University of Arizona, Tucson, AZ 85721, USA
e-mail: gsnichol@email.arizona.edu
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Scheme 1 Synthetic route to 1
1H NMR (600 MHz, CDCl3) d 7.32–7.20(m, 6H), 3.48
(s, 2H), 2.83 (d, J = 12.0 Hz, 3H), 2.01 (td, J = 11.5,
2.0 Hz, 2H), 1.94 (s, 3H), 1.78 (d, J = 12.3 Hz, 2H), 1.44
(dq, J = 3.8, 11.4 Hz, 2H). 13C NMR (150 MHz, CDCl3) d
169.72, 138.53, 129.04, 128.15, 126.92, 77.24, 77.03,
76.82, 62.98, 56.89, 51.71, 30.46, 21.17. EI-MS:m/z 248;
HRMS calcd for C14H20N3O:248.1763; found (ESI,
[M ? H]?): 248.1760.
Table 1 Crystallographic parameters for 1
Chemical formula
Formula weight
Temperature
C14H21N3O
247.34
100(2) K
˚
Radiation, wavelength
CuKa, 1.54178 A
Crystal system, space group Monoclinic, Cc
˚
a = 14.1480(3) A
Unit cell parameters
˚
b = 14.1720(4) A
˚
c = 27.6701(7) A
X-ray Crystallography
b = 96.956(1)°
3
˚
Cell volume
Z, Z0
5507.2(2) A
Single-crystal X-ray diffraction data were measured on a
Bruker Kappa APEXII DUO diffractometer with silicon-
16, 4
1.193 g/cm3
0.609 mm-1
Calculated density
Absorption coefficient l
F(000)
˚
monochromated CuKa radiation (k = 1.54178 A) and a
crystal temperature of 100 K. APEX2 was used for dif-
fractometer control and unit cell determination [7]; SAINT
was used for unit cell refinement and integration [7]; a
numerical absorption correction was applied using SAD-
ABS [8]; the structure was solved by direct methods and
refined using full-matrix least-squares on F2 with SHEL-
XTL [9]. ORTEP-3 for Windows [10] and Mercury 2.2
[11] were used for molecular graphics. All hydrogen atoms
were located in a difference Fourier map. N-bound
hydrogen atoms were freely refined; N–H distances lie in
2144
Colorless, 0.33 9 0.25 9 0.25 mm3
Crystal color and size
Reflections for cell
refinement
9959 (h range 4.8–70.4°)
Data collection method
h range for data collection
Index ranges
/ and x scans
4.4–70.5°
h -16 to 17, k -17 to 17, l -33 to 32
Completeness to h = 70.0° 98.8%
Reflections collected
Independent reflections
Reflections with F2 [ 2r
Absorption correction
29042
8212 (Rint = 0.0322)
7744
˚
the range 0.80(2)–0.86(3) A. C-bound H atoms were
refined with Uiso(H) = 1.2Ueq(C) for all hydrogen atoms
Numerical
except methyl hydrogen atoms which were refined with
Min. and max. transmission 0.8225 and 0.8627
U
iso(H) = 1.5 Ueq(C). C–H distances were constrained to
˚
1.0 A (methine), 0.99 A (methylene), 0.98 A (methyl) and
˚
0.95 A (aromatic). The value of the absolute structure
˚
˚
Structure solution
Direct methods
Full-matrix least-squares on F2
Refinement method
Weighting parameters a, b
Data/restraints/parameters
Final R indices [F2 [ 2r]
R indices (all data)
0.0456, 1.4167
parameter is based on 3041 Friedel pairs [12] (Table 1).
8212/2/686
R1 = 0.0326, wR2 = 0.0782
R1 = 0.0357, wR2 = 0.0799
1.028
Results and Discussion
Goodness-of-fit on F2
Absolute structure parameter -0.06(15)
Largest and mean shift/su 0.000 and 0.000
Largest diff. peak and hole 0.16 and -0.15 e A
Compound 1 crystallizes in the monoclinic space group Cc
with four independent molecules in the asymmetric unit
(Z’ = 4). The four molecules are shown in Fig. 1 and have
been separated for clarity. Although the ninth most com-
mon space group reported to the Cambridge Structural
Database structures in space group Cc comprise only 1.1%
of the current total (5359 out of 503348 structures as of the
-3
˚
February 2010 update [13]). Of that 1.1%, structures with
Z0 = 4 also comprise 1.1% of all reported Cc structures (60
of 5359).
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J Chem Crystallogr (2010) 40:961–964
963
Fig. 2 Least-squares overlays of molecules
A = orange, C = red, rms deviation = 0.0051 A) and B with D
A
with
C
(top,
˚
˚
(bottom, B = light blue, D = black, rms deviation = 0.007 A). In
both cases the six atoms which comprise the piperidine ring were used
for the overlay. In the printed version of the journal molecules A and
B appear as pale gray
describe some high Z0 [ 1 structures as a kinetic product of
crystallization [16], has recently been applied to this class
of structure [17–19]. The structure of 1 does not appear to
fall into any of these categories.
The four unique molecules in 1 can be split into two
pairs; by using a least-squares overlay of the six atoms
which comprise the piperidine ring we show in Fig. 2 that
molecules A and C overlay very well, as do molecules B
and D. In the case of A with C there are some small dif-
ferences between the hydrazide and phenyl groups but in
the case of B with D the overlay is excellent.
Furthermore when A and C are inverted they fit very
well onto the overlay of B with D (Fig. 3) and it is clear
that the molecules do not differ significantly in terms of
their conformation. Despite this the molecules have not
crystallized with pseudo-symmetry elements which would
relate the molecules to one-another (with a possibility of
some disorder) in the higher symmetry space group C2/c;
the structure does not solve in space group C2/c and the Cc
model cannot be converted to C2/c by applying extra
symmetry operations and deleting redundant atoms. The
value of the Flack parameter also confirms the correctness
of the space group as pseudo-inversion symmetry, for
example, would likely increase the value of the Flack
parameter.
Fig. 1 The four unique molecules in 1. Displacement ellipsoids are at
the 50% probability level and C-bound hydrogen atoms are omitted
The subject of multiple molecules in the asymmetric
unit is one of much recent interest and debate in the lit-
erature [14]. Researchers often describe such structures in
terms of packing ‘‘frustration’’ caused by competing strong
intermolecular interactions, or by some inherent chemical
property forcing molecules to crystallize with lower than
expected symmetry; witness the inability of chiral car-
boxylic acids to pack around a crystallographic inversion
center as an example of such chemical vs crystallographic
frustration [15]. In other examples molecules with con-
formational flexibility may crystallize with Z0 [ 1 and the
crystallographically unique molecules adopt very different
conformations. Other Z0 [ 1 structures are those which are
apparently related by symmetry elements not present in the
space group. The phrase ‘‘crystal on the way’’, coined to
The crystal packing consists of two hydrogen-bonded
chains which are linked together to form a thick 2D
structure. Part of the crystal packing is shown in Fig. 4. A
C22(8) chain [20] linking A with molecule B by virtue of
two unique N–HꢀꢀꢀO interactions is observed; a second
C22(8) chain links molecule C with molecule D in a similar
fashion. These two unique chains are connected to one-
another by two unique D(3) N–HꢀꢀꢀN interactions thus
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J Chem Crystallogr (2010) 40:961–964
Fig. 3 A composite overlay of all four unique molecules. Key: A, open bonds; B, dashed open bonds; C, line bonds; D, full bonds
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Supplementary Information
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CCDC 751146 contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements The diffractometer was purchased with fund-
ing from NSF grant CHE-0741837.
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