organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2056-9890

cis-1-Benzyl­pyrrolidine-2,5-dicarbo­nitrile

aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA, and bDepartment of Chemistry, University of Kentucky, Lexington, KY 40506, USA
*Correspondence e-mail: pcrooks@uky.edu

(Received 10 January 2011; accepted 18 February 2011; online 2 March 2011)

In the title compound, C13H13N3, the cyano groups at the 2- and 5-positions are eclipsed with each other. The phenyl ring is disordered over two sets of sites, with refined occupancies of 0.520 (5) and 0.480 (5). The angles between the mean plane of the pyrrolidine ring and the two cyano groups are 71.7 (9) and 75.0 (12)°.

Related literature

For Robinson–Schopf condensations with succinaldehyde, see: McIntosh (1988[McIntosh, J. M. (1988). J. Org. Chem. 53, 447-448.]). For lobelane (systematic name 2-[6-(2-hy­droxy-2-phenyl-eth­yl)-1-methyl-2-piperid­yl]-1-phenyl-ethanone) analog activity: Zheng et al. (2005[Zheng, G., Dwoskin, L. P., Deaciue, A. G., Norrholm, S. D. & Crooks, P. A. (2005). J. Med. Chem. 48, 5551-5560.]).

[Scheme 1]

Experimental

Crystal data
  • C13H13N3

  • Mr = 211.26

  • Monoclinic, P 21 /c

  • a = 10.9898 (3) Å

  • b = 9.4494 (2) Å

  • c = 11.4768 (3) Å

  • β = 103.0735 (11)°

  • V = 1160.94 (5) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 0.08 mm−1

  • T = 150 K

  • 0.24 × 0.20 × 0.16 mm

Data collection
  • Nonius KappaCCD diffractometer

  • Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]) Tmin = 0.982, Tmax = 0.988

  • 19299 measured reflections

  • 2662 independent reflections

  • 1574 reflections with I > 2σ(I)

  • Rint = 0.061

Refinement
  • R[F2 > 2σ(F2)] = 0.051

  • wR(F2) = 0.154

  • S = 1.04

  • 2662 reflections

  • 164 parameters

  • 12 restraints

  • H-atom parameters constrained

  • Δρmax = 0.17 e Å−3

  • Δρmin = −0.18 e Å−3

Data collection: COLLECT (Nonius, 1998[Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.]); cell refinement: SCALEPACK (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); data reduction: DENZO-SMN (Otwinowski & Minor, 1997[Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307-326. New York: Academic Press.]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: XP in SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); software used to prepare material for publication: SHELXL97 and local procedures.

Supporting information


Comment top

With the aim of developing lobelane analogs as potent antagonists at dihydrotetrabenazine (DTBZ) binding sites on VMAT2, and as inhibiters of [3H]-DA uptake into vesicles (Zheng et al. 2005), we have undertaken the design, synthesis and structural analysis of a series of 2,5-disubstitued phenethylpyrrolidine analogs via a key intermediate, cis-N-benzylpyrrolidine-2,5-dicarbonitrile. The primary goal of the ananlysis of the title compound is to confirm the stereochemistry of the molecule, and to obtain detailed information on the structural conformation of the molecule. The crystal X-ray studies revealed that the central pyrrolidine ring is not planar, and that the geometry of cyano groups at the C2 and C5 positions are equatorial. The angles between the exact plane defined by N1, C2, C1 and by the mean plane passing closest to the atoms of the pyrrolidinium ring (N1, C2, C3, C4, C5), and between the exact plane defined by N1, C5, C6 to the pyrrolidinium ring (N1, C2, C3, C4, C5) for the molecule are 72.48 (9)° and 75.92 (12)° respectively.

Related literature top

For Robinson–Schopf condensations with succinaldehyde, see: McIntosh (1988). For lobelane analog (systematic name 2-[6-(2-hydroxy-2-phenyl-ethyl)-1-methyl-2-piperidyl]-1-phenyl-ethanone) activity: Zheng et al. (2005).

Experimental top

The title compound was prepared by stirring a mixture of aqueous citric acid (90 ml, 0.1 M), 2,5- dimethoxytetrahydrofuran (8.3 mmol), benzylamine (4.5 mmol), and potassium cyanide (6.15 mmol) at ambient temperature for 48–72 h as per the literature procedure (McIntosh et al. 1988). The reaction mixture was then treated with excess solid sodium bicarbonate, and the reaction product extracted with dichloromethane (2x200 ml). The dichloromethane extracts were combined and dried over anhydrous sodium sulfate. The dried extract was evaporated, and chromatographed on silica gel using ethylacetate/hexane (1:9) as a eluent. From the obtained cis and trans diastereomers of N-benzylpyrrolidine-2,5-dicarbonitrile, the cis-N-benzylpyrrolidine-2,5-dicarbonitrile isomer was recrystallized from a mixture of diethyl ether and hexane (3:7) to afford a product which was suitable for single-crystal X-ray analysis. The 300-MHz proton spectrum of the cis isomer showed the benzylic protons as a clean singlet whereas in trans compound they appeared as an AB quartet. 1H NMR (CDCl3): δ 2.31 (m, 4H), 3.93 (d, j=4.1 Hz, 2H), 4.06 (s, 2H), 7.36 (m, 5H) p.p.m.; 13C NMR (DMSO-d6): δ 28.60, 51.10, 53.40, 116.90, 128.31, 128.70, 128.90, 135.20 p.p.m..

Refinement top

H atoms were found in difference Fourier maps and subsequently placed in idealized positions with constrained distances of 0.99 Å (R2CH2), 1.00 Å (R3CH), 0.95 Å (CArH), and with Uiso(H) values set to either 1.2Ueq or 1.5Ueq (RCH3) of the attached atom.

The phenyl group is disordered, and SHELXL97 commands for constraints (EADP) and restraints (SAME) were used.

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and local procedures.

Figures top
[Figure 1] Fig. 1. A view of the molecule with the atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
1-Benzylpyrrolidine-2,5-dicarbonitrile top
Crystal data top
C13H13N3F(000) = 448
Mr = 211.26Dx = 1.209 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybcCell parameters from 2818 reflections
a = 10.9898 (3) Åθ = 1.0–27.5°
b = 9.4494 (2) ŵ = 0.08 mm1
c = 11.4768 (3) ÅT = 150 K
β = 103.0735 (11)°Block, colourless
V = 1160.94 (5) Å30.24 × 0.20 × 0.16 mm
Z = 4
Data collection top
Nonius KappaCCD
diffractometer
2662 independent reflections
Radiation source: fine-focus sealed tube1574 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.061
Detector resolution: 9.1 pixels mm-1θmax = 27.5°, θmin = 1.9°
ω scans at fixed χ = 55°h = 1414
Absorption correction: multi-scan
(SCALEPACK; Otwinowski & Minor, 1997)
k = 1212
Tmin = 0.982, Tmax = 0.988l = 1414
19299 measured reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.051Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.154H-atom parameters constrained
S = 1.04 w = 1/[σ2(Fo2) + (0.0845P)2]
where P = (Fo2 + 2Fc2)/3
2662 reflections(Δ/σ)max = 0.003
164 parametersΔρmax = 0.17 e Å3
12 restraintsΔρmin = 0.18 e Å3
Crystal data top
C13H13N3V = 1160.94 (5) Å3
Mr = 211.26Z = 4
Monoclinic, P21/cMo Kα radiation
a = 10.9898 (3) ŵ = 0.08 mm1
b = 9.4494 (2) ÅT = 150 K
c = 11.4768 (3) Å0.24 × 0.20 × 0.16 mm
β = 103.0735 (11)°
Data collection top
Nonius KappaCCD
diffractometer
2662 independent reflections
Absorption correction: multi-scan
(SCALEPACK; Otwinowski & Minor, 1997)
1574 reflections with I > 2σ(I)
Tmin = 0.982, Tmax = 0.988Rint = 0.061
19299 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.05112 restraints
wR(F2) = 0.154H-atom parameters constrained
S = 1.04Δρmax = 0.17 e Å3
2662 reflectionsΔρmin = 0.18 e Å3
164 parameters
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
N10.25240 (11)0.12585 (13)0.75852 (10)0.0358 (4)
N20.23554 (17)0.03238 (18)0.46559 (13)0.0694 (5)
N30.04139 (14)0.30177 (17)0.53565 (13)0.0566 (5)
C10.24055 (16)0.01114 (17)0.56447 (15)0.0450 (5)
C20.24688 (14)0.00845 (16)0.69427 (12)0.0359 (4)
H20.32140.06730.73060.043*
C30.12832 (15)0.07866 (18)0.71691 (14)0.0449 (4)
H3A0.08110.12590.64350.054*
H3B0.14990.14990.78150.054*
C40.05140 (16)0.04144 (19)0.75352 (14)0.0480 (5)
H4A0.03270.04540.69960.058*
H4B0.04220.02800.83660.058*
C50.12448 (14)0.17649 (17)0.74314 (13)0.0386 (4)
H50.11890.24240.80990.046*
C60.07641 (14)0.24816 (17)0.62628 (14)0.0408 (4)
C70.34472 (15)0.23004 (18)0.73940 (15)0.0454 (4)
H7A0.32610.32090.77470.054*
H7B0.33240.24510.65210.054*
C80.4794 (12)0.1971 (13)0.7882 (9)0.0289 (16)0.520 (5)
C90.5668 (13)0.1649 (14)0.7247 (11)0.0361 (17)0.520 (5)
H90.54730.18050.64080.043*0.520 (5)
C100.6835 (16)0.110 (3)0.7786 (13)0.0491 (6)0.520 (5)
H100.73460.06710.73190.059*0.520 (5)
C110.7226 (12)0.1187 (14)0.8995 (13)0.049 (2)0.520 (5)
H110.80520.09200.93820.058*0.520 (5)
C120.6406 (5)0.1667 (6)0.9648 (5)0.0595 (12)0.520 (5)
H120.66770.17471.04920.071*0.520 (5)
C130.5194 (6)0.2035 (6)0.9100 (5)0.0512 (12)0.520 (5)
H130.46350.23340.95730.061*0.520 (5)
C8'0.4716 (13)0.1665 (15)0.8006 (9)0.0289 (16)0.480 (5)
C9'0.5535 (15)0.1343 (16)0.7288 (12)0.0361 (17)0.480 (5)
H9'0.52460.12790.64450.043*0.480 (5)
C10'0.6791 (18)0.111 (3)0.7824 (14)0.0491 (6)0.480 (5)
H10'0.74010.11750.73570.059*0.480 (5)
C11'0.7147 (13)0.0806 (16)0.9011 (14)0.049 (2)0.480 (5)
H11'0.79860.05450.93570.058*0.480 (5)
C12'0.6276 (6)0.0876 (7)0.9703 (6)0.0595 (12)0.480 (5)
H12'0.64940.06071.05220.071*0.480 (5)
C13'0.5090 (6)0.1337 (6)0.9200 (6)0.0512 (12)0.480 (5)
H13'0.45080.14330.96940.061*0.480 (5)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0297 (7)0.0376 (8)0.0368 (7)0.0013 (6)0.0008 (5)0.0039 (6)
N20.0964 (14)0.0703 (12)0.0454 (9)0.0083 (10)0.0246 (9)0.0027 (8)
N30.0476 (9)0.0639 (11)0.0530 (9)0.0107 (8)0.0002 (7)0.0081 (8)
C10.0508 (11)0.0431 (10)0.0412 (10)0.0029 (8)0.0104 (8)0.0039 (8)
C20.0351 (9)0.0358 (9)0.0346 (8)0.0006 (7)0.0033 (6)0.0013 (7)
C30.0418 (10)0.0463 (10)0.0455 (9)0.0057 (8)0.0076 (7)0.0018 (8)
C40.0394 (10)0.0592 (11)0.0465 (9)0.0003 (9)0.0119 (8)0.0037 (8)
C50.0332 (9)0.0471 (10)0.0337 (8)0.0036 (7)0.0039 (7)0.0040 (7)
C60.0315 (9)0.0423 (10)0.0456 (10)0.0040 (7)0.0026 (7)0.0053 (8)
C70.0397 (10)0.0376 (9)0.0545 (10)0.0036 (8)0.0015 (7)0.0029 (8)
C80.0324 (16)0.017 (5)0.0372 (19)0.010 (2)0.0068 (14)0.0011 (19)
C90.038 (3)0.030 (5)0.0419 (12)0.017 (3)0.0130 (12)0.006 (2)
C100.0422 (14)0.0482 (12)0.0622 (13)0.0031 (10)0.0231 (10)0.0089 (10)
C110.0317 (16)0.044 (7)0.0655 (13)0.003 (3)0.0006 (11)0.009 (3)
C120.0422 (17)0.090 (4)0.0402 (12)0.004 (3)0.0032 (11)0.001 (3)
C130.0392 (15)0.077 (4)0.0370 (14)0.003 (3)0.0065 (10)0.011 (3)
C8'0.0324 (16)0.017 (5)0.0372 (19)0.010 (2)0.0068 (14)0.0011 (19)
C9'0.038 (3)0.030 (5)0.0419 (12)0.017 (3)0.0130 (12)0.006 (2)
C10'0.0422 (14)0.0482 (12)0.0622 (13)0.0031 (10)0.0231 (10)0.0089 (10)
C11'0.0317 (16)0.044 (7)0.0655 (13)0.003 (3)0.0006 (11)0.009 (3)
C12'0.0422 (17)0.090 (4)0.0402 (12)0.004 (3)0.0032 (11)0.001 (3)
C13'0.0392 (15)0.077 (4)0.0370 (14)0.003 (3)0.0065 (10)0.011 (3)
Geometric parameters (Å, º) top
N1—C51.457 (2)C8—C131.369 (9)
N1—C21.4620 (19)C9—C101.392 (10)
N1—C71.465 (2)C9—H90.9500
N2—C11.1414 (19)C10—C111.359 (10)
N3—C61.1427 (17)C10—H100.9500
C1—C21.487 (2)C11—C121.373 (9)
C2—C31.536 (2)C11—H110.9500
C2—H21.0000C12—C131.383 (7)
C3—C41.530 (2)C12—H120.9500
C3—H3A0.9900C13—H130.9500
C3—H3B0.9900C8'—C13'1.374 (9)
C4—C51.527 (2)C8'—C9'1.385 (10)
C4—H4A0.9900C9'—C10'1.395 (11)
C4—H4B0.9900C9'—H9'0.9500
C5—C61.489 (2)C10'—C11'1.361 (11)
C5—H51.0000C10'—H10'0.9500
C7—C81.493 (13)C11'—C12'1.377 (10)
C7—C8'1.534 (14)C11'—H11'0.9500
C7—H7A0.9900C12'—C13'1.372 (7)
C7—H7B0.9900C12'—H12'0.9500
C8—C91.365 (9)C13'—H13'0.9500
C5—N1—C2107.16 (12)H7A—C7—H7B107.2
C5—N1—C7116.28 (12)C9—C8—C13117.0 (10)
C2—N1—C7117.31 (12)C9—C8—C7127.1 (9)
N2—C1—C2177.02 (17)C13—C8—C7115.8 (9)
N1—C2—C1112.60 (13)C8—C9—C10122.3 (10)
N1—C2—C3103.28 (12)C8—C9—H9118.9
C1—C2—C3111.96 (12)C10—C9—H9118.9
N1—C2—H2109.6C11—C10—C9118.5 (12)
C1—C2—H2109.6C11—C10—H10120.7
C3—C2—H2109.6C9—C10—H10120.7
C4—C3—C2105.59 (13)C10—C11—C12118.8 (10)
C4—C3—H3A110.6C10—C11—H11120.6
C2—C3—H3A110.6C12—C11—H11120.6
C4—C3—H3B110.6C11—C12—C13121.3 (7)
C2—C3—H3B110.6C11—C12—H12119.4
H3A—C3—H3B108.8C13—C12—H12119.4
C5—C4—C3105.40 (13)C8—C13—C12120.4 (7)
C5—C4—H4A110.7C8—C13—H13119.8
C3—C4—H4A110.7C12—C13—H13119.8
C5—C4—H4B110.7C13'—C8'—C9'117.1 (10)
C3—C4—H4B110.7C13'—C8'—C7125.5 (10)
H4A—C4—H4B108.8C9'—C8'—C7117.3 (9)
N1—C5—C6113.23 (12)C8'—C9'—C10'118.9 (11)
N1—C5—C4103.07 (13)C8'—C9'—H9'120.5
C6—C5—C4111.40 (13)C10'—C9'—H9'120.5
N1—C5—H5109.7C11'—C10'—C9'120.4 (13)
C6—C5—H5109.7C11'—C10'—H10'119.8
C4—C5—H5109.7C9'—C10'—H10'119.8
N3—C6—C5178.57 (17)C10'—C11'—C12'119.2 (12)
N1—C7—C8117.7 (4)C10'—C11'—H11'120.4
N1—C7—C8'104.9 (5)C12'—C11'—H11'120.4
N1—C7—H7A107.9C13'—C12'—C11'119.4 (8)
C8—C7—H7A107.9C13'—C12'—H12'120.3
C8'—C7—H7A113.7C11'—C12'—H12'120.3
N1—C7—H7B107.9C12'—C13'—C8'122.2 (8)
C8—C7—H7B107.9C12'—C13'—H13'118.9
C8'—C7—H7B114.9C8'—C13'—H13'118.9

Experimental details

Crystal data
Chemical formulaC13H13N3
Mr211.26
Crystal system, space groupMonoclinic, P21/c
Temperature (K)150
a, b, c (Å)10.9898 (3), 9.4494 (2), 11.4768 (3)
β (°) 103.0735 (11)
V3)1160.94 (5)
Z4
Radiation typeMo Kα
µ (mm1)0.08
Crystal size (mm)0.24 × 0.20 × 0.16
Data collection
DiffractometerNonius KappaCCD
diffractometer
Absorption correctionMulti-scan
(SCALEPACK; Otwinowski & Minor, 1997)
Tmin, Tmax0.982, 0.988
No. of measured, independent and
observed [I > 2σ(I)] reflections
19299, 2662, 1574
Rint0.061
(sin θ/λ)max1)0.649
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.051, 0.154, 1.04
No. of reflections2662
No. of parameters164
No. of restraints12
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.17, 0.18

Computer programs: COLLECT (Nonius, 1998), SCALEPACK (Otwinowski & Minor, 1997), DENZO-SMN (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), XP in SHELXTL (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008) and local procedures.

 

Acknowledgements

This research was supported by NIH grant RO1 DA13519.

References

First citationMcIntosh, J. M. (1988). J. Org. Chem. 53, 447–448.  CrossRef CAS Google Scholar
First citationNonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.  Google Scholar
First citationOtwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press.  Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationZheng, G., Dwoskin, L. P., Deaciue, A. G., Norrholm, S. D. & Crooks, P. A. (2005). J. Med. Chem. 48, 5551–5560.  Web of Science CrossRef PubMed CAS Google Scholar

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