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The identity of the title piperazinone, C8H16N2O, obtained by an unusual deoxygenation reaction, has been confirmed by its crystal structure. We describe the conformation of this template used to mimic conformationally flexible peptides and lipids and compare it to related piperazinones.
Supporting information
CCDC reference: 204694
Key indicators
- Single-crystal X-ray study
- T = 200 K
- Mean (C-C) = 0.002 Å
- R factor = 0.032
- wR factor = 0.073
- Data-to-parameter ratio = 12.3
checkCIF results
No syntax errors found
ADDSYM reports no extra symmetry
Alert Level B:
THETM_01 Alert B The value of sine(theta_max)/wavelength is less than 0.575
Calculated sin(theta_max)/wavelength = 0.5614
| Author response: The presented X-ray data of the title compound were determined in
1996 with the intention to publish them in Acta Crystallographica Section
C. However, the demands to publish in this journal increased during the
time so that the sine (theta max.)/wavelength of less then 0.575 now is no
longer sufficient for Acta Cryst. C. Unfortunately, no crystals of the
title compound do exist any longer. Therefore, we decided to submit our
article to Acta Crystallographica Section E. We hope that the presented
data are suitable for publication in this journal.
|
Alert Level C:
PLAT_420 Alert C D-H Without Acceptor N(4) - H(4) ?
General Notes
REFLT_03
From the CIF: _diffrn_reflns_theta_max 59.95
From the CIF: _reflns_number_total 1315
Count of symmetry unique reflns 789
Completeness (_total/calc) 166.67%
TEST3: Check Friedels for noncentro structure
Estimate of Friedel pairs measured 526
Fraction of Friedel pairs measured 0.667
Are heavy atom types Z>Si present no
Please check that the estimate of the number of Friedel pairs is
correct. If it is not, please give the correct count in the
_publ_section_exptl_refinement section of the submitted CIF.
0 Alert Level A = Potentially serious problem
1 Alert Level B = Potential problem
1 Alert Level C = Please check
Glassware was flame dried under an argon atmosphere and allowed to cool. Dipeptide aldehyde (III) (Kolter et al., 1992) (321.4 mg, 1 mmol) was dissolved in methanol (10 ml). After addition of a catalytic amount of palladium on charcoal (5%), the mixture was stirred under a hydrogen atmosphere for 18 h. The catalyst was filtered off and washed twice with methanol (10 ml). After evaporation of the solvent, the residue was purified by column chromatography on silicia gel (chloroform/methanol 10:1) as eluant, giving colourless crystals (yield: 32.5 mg, 20.8%) suitable for X-ray analysis. TLC: 20:1 dichloromethane–methanol, RF: 0.29; αD: −121.5° (c = 0.38; CHCl3); m.p.: 385 K; 1H NMR (400 MHz, d6-DMSO): δ 0.81 [d, J = 6.8 Hz, 3H; CH(CH3)2], 0.92 [d, J = 6.8 Hz, 3H; CH(CH3)2], 1.09 (d, J = 6.4 Hz, 3H; CH3), 2.23 [dqq, J = 3.4 Hz, J = 6.8 Hz, J = 6.8 Hz, 1H; CH(CH3)2], 2.62 (ddd, J = 0.8 Hz, J = 3.4 Hz, J = 12.4 Hz, 1H; H-5), 2.82 (dd, J = 4.0 Hz, J = 12.4 Hz, 1H; H-5), 2.98 (d, J = 3.4 Hz, 1H; H-3), 3.30 (m, 1H; H-6), 3.36 (m, br., 1H; NH), 7.62 (m, br, 1H; CONH); EI-HRMS: calculated: M+, m/z = 156.1260, found: m/z = 156.1262.
Friedel pairs are not merged. The position of the amide H atom and amine H atom was determined from a difference Fourier map and the coordinates were refined freely, with its isotropic displacement parameter constrained to Uiso(H) = 1.2Ueq(N). All remaining H atoms were treated as riding, with C—H = 0.98–1.00 Å, and Uiso(H) = 1.2Ueq(CH, CH2) and 1.5Ueq(CH3).
Data collection: CAD-4 Software (Enraf-Nonius, 1989); cell refinement: CAD-4 Software; data reduction: XCAD4 (Sheldrick, 1992); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL-NT (Sheldrick, 2001); software used to prepare material for publication: SHELXL97.
(6
S)-Methyl-3(3)-methylethyl-piperazine-2-one
top
Crystal data top
C8H16N2O | Dx = 1.171 Mg m−3 |
Mr = 156.23 | Cu Kα radiation, λ = 1.54178 Å |
Orthorhombic, P212121 | Cell parameters from 25 reflections |
a = 8.471 (2) Å | θ = 40–46° |
b = 9.282 (1) Å | µ = 0.62 mm−1 |
c = 11.271 (1) Å | T = 200 K |
V = 886.2 (2) Å3 | Block, colourless |
Z = 4 | 0.30 × 0.23 × 0.20 mm |
F(000) = 344 | |
Data collection top
Enraf-Nonius CAD-4 diffractometer | Rint = 0.073 |
Radiation source: fine-focus sealed tube | θmax = 60.0°, θmin = 6.2° |
Graphite monochromator | h = −9→9 |
ω scans | k = −10→1 |
3164 measured reflections | l = −12→12 |
1315 independent reflections | Standard reflections: 3 (orientation), 3 (intensity); every 200 (orientation) reflections |
1289 reflections with I > 2σ(I) | intensity decay: none |
Refinement top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.032 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.073 | w = 1/[σ2(Fo2) + (0.0246P)2 + 0.0864P] where P = (Fo2 + 2Fc2)/3 |
S = 1.12 | (Δ/σ)max < 0.001 |
1315 reflections | Δρmax = 0.15 e Å−3 |
107 parameters | Δρmin = −0.15 e Å−3 |
2 restraints | Extinction correction: SHELXL97, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.053 (2) |
Crystal data top
C8H16N2O | V = 886.2 (2) Å3 |
Mr = 156.23 | Z = 4 |
Orthorhombic, P212121 | Cu Kα radiation |
a = 8.471 (2) Å | µ = 0.62 mm−1 |
b = 9.282 (1) Å | T = 200 K |
c = 11.271 (1) Å | 0.30 × 0.23 × 0.20 mm |
Data collection top
Enraf-Nonius CAD-4 diffractometer | Rint = 0.073 |
3164 measured reflections | θmax = 60.0° |
1315 independent reflections | Standard reflections: 3 (orientation), 3 (intensity); every 200 (orientation) reflections |
1289 reflections with I > 2σ(I) | intensity decay: none |
Refinement top
R[F2 > 2σ(F2)] = 0.032 | 2 restraints |
wR(F2) = 0.073 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.12 | Δρmax = 0.15 e Å−3 |
1315 reflections | Δρmin = −0.15 e Å−3 |
107 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 > σ(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 | x | y | z | Uiso*/Ueq | |
N1 | 0.49978 (14) | 0.65770 (11) | 0.40547 (12) | 0.0294 (3) | |
H1 | 0.5366 (18) | 0.7065 (16) | 0.4689 (14) | 0.035* | |
C2 | 0.34366 (16) | 0.65519 (13) | 0.39126 (14) | 0.0299 (4) | |
O21 | 0.25477 (13) | 0.72369 (11) | 0.45736 (12) | 0.0482 (4) | |
C3 | 0.27706 (17) | 0.57216 (13) | 0.28589 (13) | 0.0288 (3) | |
H3 | 0.2547 | 0.6435 | 0.2215 | 0.035* | |
C31 | 0.12092 (17) | 0.49810 (13) | 0.31715 (16) | 0.0328 (4) | |
H31 | 0.0495 | 0.5723 | 0.3527 | 0.039* | |
C32 | 0.1431 (2) | 0.37890 (17) | 0.40836 (18) | 0.0458 (4) | |
H32A | 0.0401 | 0.3378 | 0.4290 | 0.069* | |
H32B | 0.1926 | 0.4187 | 0.4798 | 0.069* | |
H32C | 0.2108 | 0.3034 | 0.3751 | 0.069* | |
C33 | 0.04232 (19) | 0.4417 (2) | 0.20484 (17) | 0.0483 (5) | |
H33A | 0.0305 | 0.5206 | 0.1478 | 0.072* | |
H33B | −0.0619 | 0.4026 | 0.2245 | 0.072* | |
H33C | 0.1078 | 0.3656 | 0.1700 | 0.072* | |
N4 | 0.39153 (14) | 0.46939 (11) | 0.23979 (12) | 0.0311 (3) | |
H4 | 0.3497 (17) | 0.4296 (16) | 0.1736 (14) | 0.037* | |
C5 | 0.54484 (17) | 0.53625 (15) | 0.21980 (14) | 0.0347 (4) | |
H5A | 0.5323 | 0.6242 | 0.1711 | 0.042* | |
H5B | 0.6151 | 0.4688 | 0.1769 | 0.042* | |
C6 | 0.61544 (16) | 0.57408 (13) | 0.33786 (14) | 0.0315 (4) | |
H6 | 0.7101 | 0.6361 | 0.3238 | 0.038* | |
C61 | 0.66666 (17) | 0.44379 (16) | 0.40979 (17) | 0.0405 (4) | |
H61A | 0.7493 | 0.3916 | 0.3667 | 0.061* | |
H61B | 0.5759 | 0.3801 | 0.4224 | 0.061* | |
H61C | 0.7078 | 0.4757 | 0.4867 | 0.061* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
N1 | 0.0307 (6) | 0.0245 (5) | 0.0329 (8) | −0.0021 (5) | 0.0005 (6) | −0.0069 (5) |
C2 | 0.0321 (8) | 0.0234 (6) | 0.0343 (9) | 0.0043 (6) | −0.0009 (7) | −0.0022 (6) |
O21 | 0.0392 (7) | 0.0496 (6) | 0.0559 (9) | 0.0136 (5) | −0.0006 (6) | −0.0261 (6) |
C3 | 0.0323 (7) | 0.0265 (6) | 0.0275 (8) | 0.0032 (5) | −0.0002 (6) | 0.0021 (5) |
C31 | 0.0283 (7) | 0.0372 (7) | 0.0328 (9) | 0.0018 (5) | −0.0003 (7) | −0.0037 (6) |
C32 | 0.0453 (9) | 0.0490 (8) | 0.0430 (11) | −0.0066 (7) | 0.0064 (9) | 0.0072 (7) |
C33 | 0.0371 (9) | 0.0624 (9) | 0.0454 (12) | −0.0082 (7) | −0.0045 (8) | −0.0084 (8) |
N4 | 0.0318 (7) | 0.0301 (5) | 0.0314 (8) | −0.0039 (5) | 0.0053 (6) | −0.0090 (5) |
C5 | 0.0350 (8) | 0.0349 (6) | 0.0342 (10) | −0.0039 (6) | 0.0108 (7) | −0.0018 (6) |
C6 | 0.0286 (8) | 0.0281 (6) | 0.0379 (10) | −0.0041 (5) | 0.0080 (7) | −0.0028 (6) |
C61 | 0.0371 (8) | 0.0393 (7) | 0.0453 (10) | 0.0098 (6) | 0.0016 (8) | −0.0030 (7) |
Geometric parameters (Å, º) top
N1—C2 | 1.3324 (17) | C33—H33A | 0.9800 |
N1—C6 | 1.4639 (18) | C33—H33B | 0.9800 |
N1—H1 | 0.902 (14) | C33—H33C | 0.9800 |
C2—O21 | 1.2354 (18) | N4—C5 | 1.4568 (18) |
C2—C3 | 1.5241 (19) | N4—H4 | 0.905 (14) |
C3—N4 | 1.4561 (17) | C5—C6 | 1.501 (2) |
C3—C31 | 1.532 (2) | C5—H5A | 0.9900 |
C3—H3 | 1.0000 | C5—H5B | 0.9900 |
C31—C32 | 1.522 (2) | C6—C61 | 1.519 (2) |
C31—C33 | 1.523 (2) | C6—H6 | 1.0000 |
C31—H31 | 1.0000 | C61—H61A | 0.9800 |
C32—H32A | 0.9800 | C61—H61B | 0.9800 |
C32—H32B | 0.9800 | C61—H61C | 0.9800 |
C32—H32C | 0.9800 | | |
| | | |
C2—N1—C6 | 126.34 (12) | H33A—C33—H33B | 109.5 |
C2—N1—H1 | 116.5 (10) | C31—C33—H33C | 109.5 |
C6—N1—H1 | 116.6 (10) | H33A—C33—H33C | 109.5 |
O21—C2—N1 | 121.57 (14) | H33B—C33—H33C | 109.5 |
O21—C2—C3 | 120.30 (12) | C3—N4—C5 | 111.70 (10) |
N1—C2—C3 | 118.03 (12) | C3—N4—H4 | 107.5 (10) |
N4—C3—C2 | 111.27 (11) | C5—N4—H4 | 113.3 (10) |
N4—C3—C31 | 111.30 (10) | N4—C5—C6 | 108.53 (12) |
C2—C3—C31 | 111.55 (12) | N4—C5—H5A | 110.0 |
N4—C3—H3 | 107.5 | C6—C5—H5A | 110.0 |
C2—C3—H3 | 107.5 | N4—C5—H5B | 110.0 |
C31—C3—H3 | 107.5 | C6—C5—H5B | 110.0 |
C32—C31—C33 | 111.44 (13) | H5A—C5—H5B | 108.4 |
C32—C31—C3 | 112.02 (12) | N1—C6—C5 | 108.60 (12) |
C33—C31—C3 | 109.91 (13) | N1—C6—C61 | 109.60 (13) |
C32—C31—H31 | 107.8 | C5—C6—C61 | 113.63 (11) |
C33—C31—H31 | 107.8 | N1—C6—H6 | 108.3 |
C3—C31—H31 | 107.8 | C5—C6—H6 | 108.3 |
C31—C32—H32A | 109.5 | C61—C6—H6 | 108.3 |
C31—C32—H32B | 109.5 | C6—C61—H61A | 109.5 |
H32A—C32—H32B | 109.5 | C6—C61—H61B | 109.5 |
C31—C32—H32C | 109.5 | H61A—C61—H61B | 109.5 |
H32A—C32—H32C | 109.5 | C6—C61—H61C | 109.5 |
H32B—C32—H32C | 109.5 | H61A—C61—H61C | 109.5 |
C31—C33—H33A | 109.5 | H61B—C61—H61C | 109.5 |
C31—C33—H33B | 109.5 | | |
| | | |
C6—N1—C2—O21 | 175.79 (13) | C2—C3—C31—C33 | 168.92 (12) |
C6—N1—C2—C3 | −7.8 (2) | C2—C3—N4—C5 | −49.78 (16) |
O21—C2—C3—N4 | −164.47 (13) | C31—C3—N4—C5 | −174.87 (13) |
N1—C2—C3—N4 | 19.12 (16) | C3—N4—C5—C6 | 68.57 (15) |
O21—C2—C3—C31 | −39.53 (17) | C2—N1—C6—C5 | 24.42 (18) |
N1—C2—C3—C31 | 144.06 (13) | C2—N1—C6—C61 | −100.24 (17) |
N4—C3—C31—C32 | 58.32 (17) | N4—C5—C6—N1 | −52.05 (13) |
C2—C3—C31—C32 | −66.61 (15) | N4—C5—C6—C61 | 70.19 (15) |
N4—C3—C31—C33 | −66.15 (16) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O21i | 0.90 (1) | 2.13 (2) | 2.876 (2) | 140 (1) |
Symmetry code: (i) x+1/2, −y+3/2, −z+1. |
Experimental details
Crystal data |
Chemical formula | C8H16N2O |
Mr | 156.23 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 200 |
a, b, c (Å) | 8.471 (2), 9.282 (1), 11.271 (1) |
V (Å3) | 886.2 (2) |
Z | 4 |
Radiation type | Cu Kα |
µ (mm−1) | 0.62 |
Crystal size (mm) | 0.30 × 0.23 × 0.20 |
|
Data collection |
Diffractometer | Enraf-Nonius CAD-4 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 3164, 1315, 1289 |
Rint | 0.073 |
θmax (°) | 60.0 |
(sin θ/λ)max (Å−1) | 0.561 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.032, 0.073, 1.12 |
No. of reflections | 1315 |
No. of parameters | 107 |
No. of restraints | 2 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.15, −0.15 |
Selected geometric parameters (Å, º) topN1—C2 | 1.3324 (17) | C3—N4 | 1.4561 (17) |
N1—C6 | 1.4639 (18) | N4—C5 | 1.4568 (18) |
C2—C3 | 1.5241 (19) | C5—C6 | 1.501 (2) |
| | | |
C2—N1—C6 | 126.34 (12) | C3—N4—C5 | 111.70 (10) |
N1—C2—C3 | 118.03 (12) | N4—C5—C6 | 108.53 (12) |
N4—C3—C2 | 111.27 (11) | N1—C6—C5 | 108.60 (12) |
| | | |
C6—N1—C2—C3 | −7.8 (2) | C2—N1—C6—C61 | −100.24 (17) |
C31—C3—N4—C5 | −174.87 (13) | N4—C5—C6—C61 | 70.19 (15) |
C2—N1—C6—C5 | 24.42 (18) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O21i | 0.90 (1) | 2.13 (2) | 2.876 (2) | 139.7 (13) |
Symmetry code: (i) x+1/2, −y+3/2, −z+1. |
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The title chiral 3,6-disubstituted piperazin-2-one, (I), was obtained during the synthesis of a potential head group mimic of the natural occurring bioactive lipid ceramide. The piperazinone skeleton has been used before as a conformationally restricted analog in the synthesis of peptidomimetics (Kolter et al., 1995; Suarez-Gea et al., 1996; Schanen et al., 1996; Uchida et al., 1996). More recently, 4-N-alkylated piperazin-2-ones have been synthesized on a different route as conformationally rigid analogs of another bioactive lipid, viz. diacylglycerol (Endo et al., 1997). Compound (I) has been prepared from the protected configurationally stable dipeptide aldehyde (III) (Kolter et al., 1992) by hydrogenolysis. During this reaction, a reproducible deoxygenation of the 6-hydroxymethyl residue to a methyl group occurs as an unexpected side reaction in about 20% yield. Similar results have been obtained with starting material, where the isopropyl group is replaced by a benzyl residue (not shown). The mechanism of this reaction is not clear, but the identity of the deoxygenated compound (I) was confirmed by this crystallization experiment. Furthermore, the crystal structure gives information on the three-dimensional structure of the piperazinone scaffold and the influence of ring substituents on the ring conformation (Michel et al., 1987).
The structure of (I) with the atom numbering is shown in Fig. 1. Selected geometrical parameters are listed in Table 1. The six-membered ring system adopts a distorted half-chair conformation, with atoms N4 and C5 on opposite sides with respect to the C6/N1/C2/C3 plane. In the piperazinone, the substituents in the 3- and 6- positions are in a cisoid configuration. The methyl group shows a pseudo-axial orientation [torsion angle C2—N1—C6—C61 is −100.2 (2)°], whereas the isopropyl substituent is pseudo-equatorial orientated [the torsion angle C31—C3—N4—C5 is −174.9 (2)°]. There is one moderate intermolecular hydrogen bond (Steiner, 2002) within the crystal. This hydrogen bond, between N1—H and O21, shows a nearly linear geometry [deviation from the ideal angle: 40.3 (1)°; Table 2]. The structure of a closely related piperazin-2-one has been published before (Michel et al., 1987), in which the p-hydroxybenzyl substituent in the 3- and the ethyl carboxylate residue in the 6-position are also arranged in a cisoid configuration. We compared bond lengths and angles within the ring of (I) with those in the published structure. The deviations from the bond lengths range from 0.002 to 0.027 Å and for the angles from 0.0 to 3.2°. Therefore, although the authors proposed the contribution of a dipole–dipole interaction between these substituents, the ring conformation is very similar to (I). The structure of an additional piperazin-2-one with a trans-relationship between a 3-isopropyl and a 6-hydroxymethyl substituent has been described before (Kolter et al., 1996). Here, the ring also adopts a half-chair conformation, showing stronger distortion compared to (I) [deviation from the ideal C6/N1/C2/C3 plane dihedral angle is 1.7° greater than that of compound (I)]. Also, the hydrogen bond between the NH group and the intermolecular piperazinone oxo group shows a similar geometry. The absolute configuration of (I) could not been determined reliably [Flack (1983) parameter x = 0.2 (3)]. Therefore, (I) was assigned to agree with the chirality as established by synthesis. In the past, conformationally flexible bioactive molecules, lipids and peptides, have been mimicked by heterocycles of this type. The data on the conformation of 3,6-disubstituted piperazin-2-ones in the solid state should be helpful in the design of further lipid and peptide mimics based on this skeleton.