Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270113003806/fn3128sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270113003806/fn31281sup2.hkl | |
Chemdraw file https://doi.org/10.1107/S0108270113003806/fn31281sup3.cdx | |
Chemical Markup Language (CML) file https://doi.org/10.1107/S0108270113003806/fn31281sup4.cml |
CCDC reference: 934576
For related literature, see: Dittrich et al. (2005, 2006); Frankel & Young (1998); Hübschle et al. (2007); Hansen & Coppens (1978); Min et al. (2010); Moir et al. (2011); Momma & Izumi (2011); Nair & Chi (2007); Nair et al. (2006); Newton et al. (2005); Pommier et al. (2005); Rhodes et al. (2011); Seo et al. (2011); Shimura & Kodama (2009); Summa (2008); Taktakishvili et al. (2000); Volkov et al. (2006).
The integrase inhibitor was prepared from the coupling of the corresponding diketo acid (Seo et al., 2011) and 1-amino-2-pyrolidinone p-toluenesulfonate. The title compound crystallized from dichloromethane as yellow prisms (yield 78%; m.p. 448–449 K). UV (CH3OH, λ, nm): 401 (ε 9, 139), 318 (ε 6, 225). HRMS, calculated for C27H22F3N3O5: [M + H]+ 526.1590; found: 526.1589.
The program InvariomTool (Hübschle et al., 2007) was used to prepare master and input files for an invariom refinement with the XDLSM program [Software reference?] of the XD suite [Software reference?]. The program assigns invarioms to all atoms in a given crystal structure by examining the connectivity in terms of nearest or next-nearest neighbors. Nonspherical valence scattering contributions for atoms in an environment of single bonds were obtained from theoretical calculations on model compounds that included nearest-neighbour atoms, whereas for H atoms and atoms in a delocalized chemical environment the model compounds also included the next-nearest neighbor atoms. Several fragments were not present in the invariom database. New scattering factors for these fragments, including the keto–enol group, were calculated from geometry optimizations at the B3LYP/D95++(3df,3 pd) level of theory [Software reference?] and included in the invariom database to increase its coverage of chemical environments. Full-matrix least-squares refinements on F2 using complete multipole expansions were carried out with the program XDLSM using statistical weights. Only reflections with intensities I > 3σ(I) were included in the refinement. Initially, bond lengths involving H atoms were set to the X—H distances obtained from model compounds that included the next-nearest neighbours of the H atom of interest. This procedure gives longer distances that are closer to neutron-determined distances [Standard reference?]. However, in the final cycles, these atom positions were refined freely. Positional and displacement parameters (isotropic and anisotropic for non-H atoms) were refined, but no multipole parameters. However, a hexadecapolar level of the multipole expansion was used for all atoms. A molecular electroneutrality constraint was applied. The introduction of invarioms improved R(F) from 0.0511 to 0.0349 while using the same weighting scheme {w = 1/[σ2(Fo2)]} as the spherical-atom refinement, and improved the goodness-of-fit from 2.832 to 2.001.
Data collection: APEX2 (Bruker, 2011); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008a); program(s) used to refine structure: XD2006 (Volkov et al., 2006); molecular graphics: XD2006 (Volkov et al., 2006), VESTA (Momma & Izumi, 2011) and OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: XD2006 (Volkov et al., 2006).
C27H22F3N3O5 | Z = 2 |
Mr = 525.48 | F(000) = 544 |
Triclinic, P1 | Dx = 1.469 Mg m−3 |
Hall symbol: -P 1 | Mo Kα radiation, λ = 0.71073 Å |
a = 8.8182 (10) Å | Cell parameters from 7934 reflections |
b = 11.5986 (13) Å | θ = 2.3–30.8° |
c = 12.2741 (14) Å | µ = 0.12 mm−1 |
α = 98.594 (2)° | T = 173 K |
β = 90.904 (2)° | Prism, yellow |
γ = 106.435 (2)° | 0.75 × 0.65 × 0.35 mm |
V = 1188.3 (2) Å3 |
Bruker APEXII area-detector diffractometer | 5447 independent reflections |
Radiation source: fine-focus sealed tube | 5175 reflections with I > 3σ(I) |
Graphite monochromator | Rint = 0.029 |
Detector resolution: 512 pixels mm-1 | θmax = 29.6°, θmin = 1.7° |
ω scans with a narrow frame width | h = −11→11 |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 2008b) | k = −15→15 |
Tmin = 0.841, Tmax = 1.000 | l = −15→15 |
22962 measured reflections |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.035 | Hydrogen site location: difference Fourier map |
wR(F2) = 0.067 | All H-atom parameters refined |
S = 2.00 | w2 = 1/[s2(Fo2)] |
5175 reflections | (Δ/σ)max = 0.001 |
431 parameters | Δρmax = 0.24 e Å−3 |
0 restraints | Δρmin = −0.19 e Å−3 |
0 constraints |
C27H22F3N3O5 | γ = 106.435 (2)° |
Mr = 525.48 | V = 1188.3 (2) Å3 |
Triclinic, P1 | Z = 2 |
a = 8.8182 (10) Å | Mo Kα radiation |
b = 11.5986 (13) Å | µ = 0.12 mm−1 |
c = 12.2741 (14) Å | T = 173 K |
α = 98.594 (2)° | 0.75 × 0.65 × 0.35 mm |
β = 90.904 (2)° |
Bruker APEXII area-detector diffractometer | 5447 independent reflections |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 2008b) | 5175 reflections with I > 3σ(I) |
Tmin = 0.841, Tmax = 1.000 | Rint = 0.029 |
22962 measured reflections |
R[F2 > 2σ(F2)] = 0.035 | 0 restraints |
wR(F2) = 0.067 | All H-atom parameters refined |
S = 2.00 | Δρmax = 0.24 e Å−3 |
5175 reflections | Δρmin = −0.19 e Å−3 |
431 parameters |
Experimental. Absorption correction: SADABS-2008/1 (Sheldrick, 2008b) was used for absorption correction. R(int) was 0.0701 before and 0.0457 after correction. The ratio of minimum to maximum transmission is 0.8414. The λ/2 correction factor is 0.0015. |
Refinement. An invariom refinement was performed (Dittrich, Acta Cryst. A62, 217). This improves the positional and thermal parameters compared to an independent-atom refinement. Using non-spherical scattering factors improves the standard uncertainties of H-atom coordinates. |
x | y | z | Uiso*/Ueq | ||
F36 | 0.43508 (7) | 0.48237 (5) | 0.20138 (5) | 0.040 | |
F37 | 1.10909 (8) | 0.35495 (6) | 0.30948 (6) | 0.056 | |
F38 | 0.69726 (8) | 0.51711 (6) | 0.41718 (7) | 0.056 | |
O8 | 0.61975 (9) | 0.03150 (7) | −0.37267 (6) | 0.040 | |
O9 | 0.89472 (8) | 0.07428 (6) | −0.55828 (6) | 0.030 | |
O11 | 0.92594 (8) | 0.00319 (7) | −0.20485 (6) | 0.032 | |
O14 | 0.89726 (8) | 0.08095 (7) | −0.00493 (6) | 0.031 | |
O21 | 0.44806 (8) | 0.13856 (6) | −0.05132 (6) | 0.032 | |
N1 | 0.74444 (9) | −0.10877 (7) | −0.51980 (7) | 0.026 | |
N6 | 0.78886 (10) | −0.08321 (8) | −0.40847 (7) | 0.027 | |
N17 | 0.47097 (9) | 0.22606 (7) | 0.12787 (7) | 0.026 | |
C2 | 0.59985 (13) | −0.20406 (10) | −0.56282 (9) | 0.030 | |
C3 | 0.60702 (14) | −0.20228 (11) | −0.68715 (10) | 0.034 | |
C4 | 0.70382 (13) | −0.07230 (10) | −0.69638 (9) | 0.031 | |
C5 | 0.79433 (11) | −0.02298 (9) | −0.58611 (8) | 0.025 | |
C7 | 0.72582 (12) | −0.00616 (9) | −0.34317 (8) | 0.026 | |
C10 | 0.79722 (11) | 0.02670 (9) | −0.22452 (8) | 0.025 | |
C12 | 0.71226 (12) | 0.07741 (9) | −0.14522 (8) | 0.027 | |
C13 | 0.76709 (11) | 0.10337 (9) | −0.03424 (8) | 0.025 | |
C15 | 0.68748 (11) | 0.15791 (8) | 0.05478 (8) | 0.023 | |
C16 | 0.53049 (11) | 0.17108 (8) | 0.03520 (8) | 0.025 | |
C18 | 0.55138 (13) | 0.26522 (9) | 0.22759 (9) | 0.027 | |
C19 | 0.69925 (12) | 0.25366 (9) | 0.24642 (8) | 0.026 | |
C20 | 0.76563 (12) | 0.19723 (9) | 0.15766 (8) | 0.025 | |
C22 | 0.30840 (12) | 0.23427 (10) | 0.11434 (10) | 0.028 | |
C23 | 0.29157 (11) | 0.33550 (9) | 0.05620 (8) | 0.027 | |
C24 | 0.34957 (12) | 0.45652 (9) | 0.10419 (9) | 0.030 | |
C25 | 0.32205 (15) | 0.55113 (11) | 0.05877 (10) | 0.039 | |
C26 | 0.23228 (15) | 0.52338 (12) | −0.04004 (11) | 0.045 | |
C27 | 0.17407 (15) | 0.40330 (12) | −0.09244 (11) | 0.044 | |
C28 | 0.20515 (13) | 0.31053 (11) | −0.04469 (9) | 0.035 | |
C29 | 0.78772 (14) | 0.30277 (10) | 0.35756 (9) | 0.030 | |
C30 | 0.89726 (12) | 0.42953 (9) | 0.36200 (8) | 0.029 | |
C31 | 1.05463 (14) | 0.45206 (10) | 0.33765 (9) | 0.037 | |
C32 | 1.15813 (17) | 0.56781 (12) | 0.34235 (10) | 0.045 | |
C33 | 1.10320 (17) | 0.66716 (12) | 0.37361 (10) | 0.045 | |
C34 | 0.94689 (17) | 0.65072 (11) | 0.39929 (10) | 0.044 | |
C35 | 0.84898 (13) | 0.53338 (10) | 0.39215 (9) | 0.036 | |
H14 | 0.936 (2) | 0.0436 (16) | −0.0830 (15) | 0.053 (5) | |
H6 | 0.8968 (15) | −0.0894 (11) | −0.3899 (10) | 0.036 (3) | |
H2A | 0.5006 (14) | −0.1793 (10) | −0.5299 (9) | 0.038 (3) | |
H2B | 0.6042 (13) | −0.2869 (11) | −0.5403 (9) | 0.041 (3) | |
H3A | 0.4934 (16) | −0.2245 (11) | −0.7261 (11) | 0.054 (4) | |
H3B | 0.6686 (15) | −0.2627 (12) | −0.7202 (11) | 0.050 (4) | |
H4A | 0.7850 (15) | −0.0637 (11) | −0.7592 (11) | 0.054 (4) | |
H4B | 0.6282 (15) | −0.0147 (12) | −0.7042 (11) | 0.055 (4) | |
H12 | 0.6069 (14) | 0.0930 (10) | −0.1683 (10) | 0.039 (3) | |
H18 | 0.4929 (13) | 0.3053 (11) | 0.2901 (10) | 0.039 (3) | |
H20 | 0.8849 (14) | 0.1866 (10) | 0.1697 (10) | 0.038 (3) | |
H22A | 0.2669 (14) | 0.2444 (10) | 0.1953 (11) | 0.039 (3) | |
H22B | 0.2365 (14) | 0.1492 (12) | 0.0699 (10) | 0.037 (3) | |
H25 | 0.3690 (16) | 0.6390 (13) | 0.0960 (12) | 0.058 (4) | |
H26 | 0.2090 (15) | 0.5964 (13) | −0.0762 (12) | 0.059 (4) | |
H27 | 0.1059 (17) | 0.3832 (13) | −0.1684 (13) | 0.067 (5) | |
H28 | 0.1608 (14) | 0.2165 (12) | −0.0843 (11) | 0.047 (4) | |
H29A | 0.7030 (14) | 0.3050 (10) | 0.4217 (10) | 0.013 (3) | |
H29B | 0.8555 (13) | 0.2408 (11) | 0.3777 (9) | 0.012 (3) | |
H32 | 1.2722 (16) | 0.5736 (12) | 0.3248 (12) | 0.058 (4) | |
H33 | 1.1802 (16) | 0.7552 (13) | 0.3791 (11) | 0.060 (4) | |
H34 | 0.9033 (16) | 0.7221 (14) | 0.4222 (12) | 0.064 (5) |
U11 | U22 | U33 | U12 | U13 | U23 | |
F36 | 0.0471 (4) | 0.0312 (4) | 0.0363 (4) | 0.0096 (3) | −0.0060 (3) | −0.0037 (3) |
F37 | 0.0528 (4) | 0.0452 (4) | 0.0686 (5) | 0.0202 (4) | 0.0188 (4) | −0.0092 (4) |
F38 | 0.0463 (4) | 0.0451 (4) | 0.0762 (6) | 0.0249 (3) | −0.0070 (4) | −0.0091 (4) |
O8 | 0.0446 (5) | 0.0544 (5) | 0.0282 (4) | 0.0321 (4) | −0.0023 (3) | −0.0024 (4) |
O9 | 0.0286 (4) | 0.0259 (4) | 0.0354 (4) | 0.0079 (3) | 0.0004 (3) | 0.0014 (3) |
O11 | 0.0268 (4) | 0.0433 (4) | 0.0259 (4) | 0.0141 (3) | 0.0019 (3) | −0.0003 (3) |
O14 | 0.0270 (4) | 0.0352 (4) | 0.0283 (4) | 0.0103 (3) | −0.0016 (3) | −0.0021 (3) |
O21 | 0.0284 (4) | 0.0382 (4) | 0.0270 (4) | 0.0114 (3) | −0.0034 (3) | −0.0075 (3) |
N1 | 0.0255 (4) | 0.0284 (5) | 0.0239 (4) | 0.0084 (4) | 0.0012 (3) | 0.0000 (4) |
N6 | 0.0282 (5) | 0.0314 (5) | 0.0232 (5) | 0.0126 (4) | 0.0005 (4) | −0.0001 (4) |
N17 | 0.0286 (4) | 0.0227 (4) | 0.0250 (5) | 0.0082 (4) | 0.0032 (4) | 0.0005 (4) |
C2 | 0.0290 (6) | 0.0268 (6) | 0.0322 (6) | 0.0064 (5) | −0.0010 (5) | 0.0006 (5) |
C3 | 0.0362 (6) | 0.0333 (6) | 0.0305 (6) | 0.0099 (5) | −0.0038 (5) | −0.0038 (5) |
C4 | 0.0285 (6) | 0.0372 (6) | 0.0253 (6) | 0.0085 (5) | 0.0000 (4) | 0.0015 (5) |
C5 | 0.0235 (5) | 0.0273 (5) | 0.0248 (5) | 0.0106 (4) | 0.0010 (4) | 0.0007 (4) |
C7 | 0.0289 (5) | 0.0291 (5) | 0.0222 (5) | 0.0122 (4) | 0.0009 (4) | 0.0011 (4) |
C10 | 0.0276 (5) | 0.0275 (5) | 0.0210 (5) | 0.0098 (4) | 0.0014 (4) | 0.0008 (4) |
C12 | 0.0302 (5) | 0.0302 (6) | 0.0222 (5) | 0.0134 (4) | 0.0010 (4) | −0.0003 (4) |
C13 | 0.0272 (5) | 0.0232 (5) | 0.0230 (5) | 0.0070 (4) | 0.0023 (4) | −0.0012 (4) |
C15 | 0.0266 (5) | 0.0216 (5) | 0.0213 (5) | 0.0082 (4) | 0.0007 (4) | −0.0012 (4) |
C16 | 0.0262 (5) | 0.0227 (5) | 0.0239 (5) | 0.0068 (4) | 0.0009 (4) | −0.0013 (4) |
C18 | 0.0352 (6) | 0.0248 (5) | 0.0226 (5) | 0.0113 (4) | 0.0038 (5) | 0.0014 (4) |
C19 | 0.0349 (6) | 0.0241 (5) | 0.0200 (5) | 0.0108 (4) | −0.0002 (4) | 0.0004 (4) |
C20 | 0.0317 (5) | 0.0227 (5) | 0.0218 (5) | 0.0092 (4) | −0.0004 (4) | 0.0003 (4) |
C22 | 0.0285 (5) | 0.0242 (6) | 0.0317 (6) | 0.0076 (4) | 0.0063 (5) | 0.0036 (5) |
C23 | 0.0270 (5) | 0.0235 (5) | 0.0285 (6) | 0.0076 (4) | 0.0038 (4) | 0.0015 (4) |
C24 | 0.0335 (5) | 0.0243 (6) | 0.0304 (6) | 0.0082 (4) | 0.0043 (4) | 0.0014 (5) |
C25 | 0.0525 (7) | 0.0244 (6) | 0.0381 (7) | 0.0095 (5) | 0.0021 (6) | 0.0045 (5) |
C26 | 0.0594 (8) | 0.0355 (7) | 0.0442 (8) | 0.0146 (6) | 0.0002 (6) | 0.0146 (6) |
C27 | 0.0535 (8) | 0.0422 (8) | 0.0355 (7) | 0.0110 (6) | −0.0064 (6) | 0.0087 (6) |
C28 | 0.0396 (6) | 0.0302 (6) | 0.0308 (6) | 0.0060 (5) | −0.0018 (5) | 0.0013 (5) |
C29 | 0.0425 (6) | 0.0277 (6) | 0.0208 (6) | 0.0122 (5) | −0.0015 (5) | 0.0012 (4) |
C30 | 0.0403 (6) | 0.0263 (5) | 0.0206 (5) | 0.0130 (5) | −0.0026 (4) | −0.0015 (4) |
C31 | 0.0448 (7) | 0.0346 (6) | 0.0292 (6) | 0.0111 (5) | 0.0057 (5) | −0.0033 (5) |
C32 | 0.0493 (8) | 0.0425 (8) | 0.0358 (7) | 0.0032 (6) | 0.0076 (6) | −0.0012 (6) |
C33 | 0.0635 (9) | 0.0314 (7) | 0.0318 (6) | 0.0031 (6) | −0.0076 (6) | 0.0027 (5) |
C34 | 0.0631 (9) | 0.0278 (7) | 0.0400 (7) | 0.0179 (6) | −0.0166 (6) | −0.0039 (5) |
C35 | 0.0462 (7) | 0.0292 (6) | 0.0342 (6) | 0.0168 (5) | −0.0090 (5) | −0.0033 (5) |
F36—C24 | 1.3484 (12) | C18—C19 | 1.3676 (14) |
F37—C31 | 1.3467 (13) | C18—H18 | 1.055 (13) |
F38—C35 | 1.3444 (13) | C19—C20 | 1.4078 (14) |
O8—C7 | 1.2102 (11) | C19—C29 | 1.5088 (14) |
O9—C5 | 1.2178 (12) | C20—H20 | 1.104 (12) |
O11—C10 | 1.2678 (11) | C22—C23 | 1.5017 (14) |
O14—C13 | 1.3033 (12) | C22—H22A | 1.066 (13) |
O21—C16 | 1.2245 (11) | C22—H22B | 1.072 (13) |
N1—N6 | 1.3802 (11) | C23—C24 | 1.3842 (14) |
N1—C2 | 1.4605 (13) | C23—C28 | 1.3915 (15) |
N1—C5 | 1.3608 (12) | C24—C25 | 1.3795 (15) |
N6—C7 | 1.3531 (13) | C25—C26 | 1.3820 (17) |
N6—H6 | 1.000 (12) | C25—H25 | 1.017 (14) |
N17—C16 | 1.4026 (12) | C26—C27 | 1.3908 (18) |
N17—C18 | 1.3533 (13) | C26—H26 | 1.079 (14) |
C2—C3 | 1.5313 (16) | C27—C28 | 1.3881 (16) |
C2—H2A | 1.063 (12) | C27—H27 | 1.059 (15) |
C2—H2B | 1.050 (12) | C28—H28 | 1.083 (13) |
C3—C4 | 1.5297 (16) | C29—C30 | 1.5061 (15) |
C3—H3A | 1.049 (13) | C29—H29A | 1.097 (13) |
C3—H3B | 1.043 (14) | C29—H29B | 1.107 (12) |
C4—C5 | 1.5074 (14) | C30—C31 | 1.3838 (15) |
C4—H4A | 1.057 (14) | C30—C35 | 1.3895 (15) |
C4—H4B | 1.082 (14) | C31—C32 | 1.3858 (16) |
C7—C10 | 1.5271 (14) | C32—C33 | 1.3782 (19) |
C10—C12 | 1.3986 (14) | C32—H32 | 1.018 (14) |
C12—C13 | 1.3979 (14) | C33—C34 | 1.3851 (19) |
C12—H12 | 1.038 (12) | C33—H33 | 1.046 (14) |
C13—C15 | 1.4682 (14) | C34—C35 | 1.3793 (16) |
C15—C16 | 1.4553 (13) | C34—H34 | 1.013 (15) |
C15—C20 | 1.3784 (13) | ||
N6—N1—C2 | 121.04 (8) | C18—C19—C29 | 120.67 (10) |
N6—N1—C5 | 120.87 (8) | C20—C19—C29 | 121.98 (9) |
C2—N1—C5 | 113.84 (8) | C15—C20—C19 | 121.74 (9) |
N1—N6—C7 | 118.08 (8) | C15—C20—H20 | 118.8 (6) |
N1—N6—H6 | 114.6 (7) | C19—C20—H20 | 119.4 (6) |
C7—N6—H6 | 120.9 (7) | C23—C22—H22A | 110.3 (6) |
C16—N17—C18 | 123.69 (9) | C23—C22—H22B | 109.0 (6) |
N1—C2—C3 | 101.58 (8) | H22A—C22—H22B | 107.5 (9) |
N1—C2—H2A | 109.0 (6) | C22—C23—C24 | 121.77 (10) |
N1—C2—H2B | 109.4 (6) | C22—C23—C28 | 120.88 (10) |
C3—C2—H2A | 112.5 (6) | C24—C23—C28 | 117.14 (10) |
C3—C2—H2B | 113.5 (7) | F36—C24—C23 | 117.88 (9) |
H2A—C2—H2B | 110.4 (8) | F36—C24—C25 | 118.66 (10) |
C2—C3—C4 | 104.61 (9) | C23—C24—C25 | 123.45 (10) |
C2—C3—H3A | 111.5 (7) | C24—C25—C26 | 118.15 (11) |
C2—C3—H3B | 108.3 (7) | C24—C25—H25 | 120.8 (8) |
C4—C3—H3A | 111.7 (7) | C26—C25—H25 | 121.0 (8) |
C4—C3—H3B | 109.2 (7) | C25—C26—C27 | 120.47 (11) |
H3A—C3—H3B | 111.3 (10) | C25—C26—H26 | 118.9 (7) |
C3—C4—C5 | 105.07 (9) | C27—C26—H26 | 120.6 (7) |
C3—C4—H4A | 115.9 (7) | C26—C27—C28 | 119.79 (12) |
C3—C4—H4B | 111.4 (7) | C26—C27—H27 | 119.8 (8) |
C5—C4—H4A | 108.8 (7) | C28—C27—H27 | 120.4 (8) |
C5—C4—H4B | 105.5 (7) | C23—C28—C27 | 120.97 (11) |
H4A—C4—H4B | 109.5 (10) | C23—C28—H28 | 118.2 (7) |
O9—C5—N1 | 124.55 (9) | C27—C28—H28 | 120.8 (7) |
O9—C5—C4 | 128.21 (9) | C19—C29—C30 | 112.22 (8) |
N1—C5—C4 | 107.24 (9) | C19—C29—H29A | 109.6 (6) |
O8—C7—N6 | 124.60 (10) | C19—C29—H29B | 109.8 (6) |
O8—C7—C10 | 121.88 (9) | C30—C29—H29A | 108.4 (6) |
N6—C7—C10 | 113.48 (8) | C30—C29—H29B | 110.0 (6) |
O11—C10—C7 | 117.89 (9) | H29A—C29—H29B | 106.6 (8) |
O11—C10—C12 | 125.07 (9) | C29—C30—C31 | 122.72 (10) |
C7—C10—C12 | 117.02 (9) | C29—C30—C35 | 122.73 (10) |
C10—C12—C13 | 119.72 (9) | C31—C30—C35 | 114.55 (10) |
C10—C12—H12 | 120.1 (7) | F37—C31—C30 | 117.32 (10) |
C13—C12—H12 | 120.1 (7) | F37—C31—C32 | 118.89 (11) |
O14—C13—C12 | 120.11 (9) | C30—C31—C32 | 123.78 (11) |
O14—C13—C15 | 116.09 (9) | C31—C32—C33 | 118.85 (13) |
C12—C13—C15 | 123.79 (9) | C31—C32—H32 | 117.1 (8) |
C13—C15—C16 | 121.08 (9) | C33—C32—H32 | 124.1 (8) |
C13—C15—C20 | 118.32 (9) | C32—C33—C34 | 120.18 (12) |
C16—C15—C20 | 120.60 (9) | C32—C33—H33 | 119.9 (8) |
O21—C16—N17 | 118.61 (9) | C34—C33—H33 | 119.9 (8) |
O21—C16—C15 | 127.00 (9) | C33—C34—C35 | 118.40 (12) |
N17—C16—C15 | 114.39 (9) | C33—C34—H34 | 121.8 (8) |
N17—C18—C19 | 122.22 (10) | C35—C34—H34 | 119.8 (8) |
N17—C18—H18 | 115.8 (6) | F38—C35—C30 | 117.21 (10) |
C19—C18—H18 | 122.0 (6) | F38—C35—C34 | 118.54 (10) |
C18—C19—C20 | 117.33 (10) | C30—C35—C34 | 124.24 (12) |
D—H···A | D—H | H···A | D···A | D—H···A |
N6—H6···O9i | 1.00 (1) | 1.92 (1) | 2.8014 (12) | 145 (1) |
O14—H14···O11 | 1.09 (2) | 1.49 (2) | 2.5270 (11) | 156 (2) |
C4—H4A···O11i | 1.06 (1) | 2.51 (1) | 3.4214 (14) | 144 (1) |
C4—H4B···O8ii | 1.08 (1) | 2.36 (1) | 3.1312 (15) | 127 (1) |
C12—H12···O21 | 1.04 (1) | 2.14 (1) | 2.8346 (13) | 123 (1) |
C22—H22A···F37iii | 1.07 (1) | 2.47 (1) | 3.3627 (14) | 141 (1) |
C22—H22B···O14iv | 1.07 (1) | 2.59 (1) | 3.6281 (14) | 163 (1) |
C29—H29B···O9v | 1.11 (1) | 2.30 (1) | 3.3441 (14) | 156 (1) |
C32—H32···F36vi | 1.02 (2) | 2.44 (2) | 3.3062 (16) | 143 (1) |
Symmetry codes: (i) −x+2, −y, −z−1; (ii) −x+1, −y, −z−1; (iii) x−1, y, z; (iv) −x+1, −y, −z; (v) x, y, z+1; (vi) x+1, y, z. |
Experimental details
Crystal data | |
Chemical formula | C27H22F3N3O5 |
Mr | 525.48 |
Crystal system, space group | Triclinic, P1 |
Temperature (K) | 173 |
a, b, c (Å) | 8.8182 (10), 11.5986 (13), 12.2741 (14) |
α, β, γ (°) | 98.594 (2), 90.904 (2), 106.435 (2) |
V (Å3) | 1188.3 (2) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.12 |
Crystal size (mm) | 0.75 × 0.65 × 0.35 |
Data collection | |
Diffractometer | Bruker APEXII area-detector diffractometer |
Absorption correction | Empirical (using intensity measurements) (SADABS; Sheldrick, 2008b) |
Tmin, Tmax | 0.841, 1.000 |
No. of measured, independent and observed [I > 3σ(I)] reflections | 22962, 5447, 5175 |
Rint | 0.029 |
(sin θ/λ)max (Å−1) | 0.694 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.035, 0.067, 2.00 |
No. of reflections | 5175 |
No. of parameters | 431 |
H-atom treatment | All H-atom parameters refined |
Δρmax, Δρmin (e Å−3) | 0.24, −0.19 |
Computer programs: APEX2 (Bruker, 2011), SAINT (Bruker, 2009), SHELXS97 (Sheldrick, 2008a), XD2006 (Volkov et al., 2006), VESTA (Momma & Izumi, 2011) and OLEX2 (Dolomanov et al., 2009).
F36—C24 | 1.3484 (12) | N6—C7 | 1.3531 (13) |
F37—C31 | 1.3467 (13) | C7—C10 | 1.5271 (14) |
F38—C35 | 1.3444 (13) | C10—C12 | 1.3986 (14) |
O8—C7 | 1.2102 (11) | C12—C13 | 1.3979 (14) |
O9—C5 | 1.2178 (12) | C12—H12 | 1.038 (12) |
O11—C10 | 1.2678 (11) | C13—C15 | 1.4682 (14) |
O14—C13 | 1.3033 (12) | C15—C16 | 1.4553 (13) |
O21—C16 | 1.2245 (11) | C15—C20 | 1.3784 (13) |
N1—N6 | 1.3802 (11) | C18—C19 | 1.3676 (14) |
N1—C2 | 1.4605 (13) | C19—C20 | 1.4078 (14) |
N1—C5 | 1.3608 (12) | ||
O11—C10—C7 | 117.89 (9) | C13—C12—H12 | 120.1 (7) |
O11—C10—C12 | 125.07 (9) | O14—C13—C12 | 120.11 (9) |
C7—C10—C12 | 117.02 (9) | O14—C13—C15 | 116.09 (9) |
C10—C12—C13 | 119.72 (9) | C12—C13—C15 | 123.79 (9) |
C10—C12—H12 | 120.1 (7) |
D—H···A | D—H | H···A | D···A | D—H···A |
N6—H6···O9i | 1.000 (14) | 1.924 (14) | 2.8014 (12) | 144.8 (10) |
O14—H14···O11 | 1.092 (18) | 1.492 (18) | 2.5270 (11) | 155.5 (16) |
C12—H12···O21 | 1.038 (13) | 2.135 (12) | 2.8346 (13) | 122.7 (9) |
Symmetry code: (i) −x+2, −y, −z−1. |
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The retroviral enzyme HIV-1 integrase is essential for HIV replication and is a significant target for the discovery and development of anti-HIV therapeutic agents (Moir et al., 2011; Frankel & Young, 1998; Nair & Chi, 2007; Pommier et al., 2005). Research efforts on anti-HIV integrase inhibitors for the treatment of acquired immunodeficiency syndrome (AIDS) has resulted in several anti-HIV agents, two of which, raltegravir and elvitegravir, have been approved by the US Food and Drug Administration for the clinical treatment of HIV–AIDS (Nair et al., 2006; Summa et al., 2008; Min et al., 2010; Shimura & Kodama, 2009; Taktakishvili et al., 2000). The crystallographic structures of some HIV integrase inhibitors have been reported [see, for example, Rhodes et al. (2011) and Newton et al. (2005)]. As resistance, toxicity and drug–drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of new anti-HIV active integrase inhibitors remains a significant scientific challenge. The compound (Z)-4-[5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide, (1), discovered in our laboratory, is an integrase inhibitor which possesses potent (low nM) anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. However, this compound can exist in three possible forms (I, II and III) with respect to the β-diketo functionality (see Scheme 1). In order to determine which tautomeric form is dominant in the solid state, the single-crystal X-ray structure of integrase inhibitor (1) was undertaken. An invariom refinement (Dittrich et al., 2005; Hansen & Coppens, 1978) was performed to examine the electrostatic properties of the molecule in further detail.
The molecular structure of (1) contains a variety of distinct groups including a central pyridinone ring, fluorobenzene rings, a keto–enol group and a 2-oxopyrrolidin-1-yl group (Fig. 1 and Table 1). The scattering factors of some fragments were not yet present in the invariom database (Dittrich et al., 2006) and were calculated here using quantum mechanics. This method of refinement led to C—H distances somewhat longer [1.013 (15)–1.107 (12) Å] than ordinarily expected from an X-ray determination but closer to distances determined from neutron diffraction [Standard reference?].
The H atom in the strong intramolecular hydrogen bond is not symmetrically located between the two O-atom centers but rather favors atom O14 over O11, i.e. form I is the dominant form in the solid. This is reflected by the longer C—O bond for O14 [1.3033 (12) Å, compared with 1.2678 (11) Å for O11] [Values amended to match CIF tables - please confirm]. However, this is not a completely localized H atom and there is some residual disorder. This was seen in the residual electron-density map about atom O11, with a maximum peak height of 0.24 e Å-3 (Fig. 2). A deformation electron-density map (with contour step values of ±0.05 e Å-3) is shown in Fig. 3. The hydrogen bond is not linear: the O14—H14···O11 angle is 155.5 (16)° (Table 2). The H atom on atom N6 donates an intermolecular hydrogen bond to atom O9 (N6—H6···O9), forming a centrosymmetric dimer. The slightly acidic α-C—H H atom of the keto–enol group donates a weak intramolecular hydrogen bond to carbonyl atom O21 (C12—H12···O21; see Table 2 for details).
Since a complete static electron-density distribution is available from the invariom model scattering factors, various properties like the dipole moment and electrostatic potential [V(r)] can be derived from the electron density. They were calculated using the program XDPROP in XD2006 (Volkov et al., 2006). The results could provide information on the capacity of this molecule to interact with a protein-binding site. The dipole moment (p) for the molecule calculated from the multipole populations is 12.06 D. The electrostatic field is the force that a hypothetical proton would be subjected to if it were present. The electrostatic potential (a scalar quantity) at a given point can be defined as the amount of work that is needed to bring a unit of charge from infinity to that point. A composite of the electrostatic potential mapped onto the electron-density isosurface (0.1 e Å-3) using the program VESTA (Momma & Izumi, 2011) is shown in Fig. 4. Atom H14, involved in a strong intramolecular hydrogen bond, shows a strong positive potential, while adjacent atom O11 shows a strong negative potential. [Unfortunately, the colours are indistinguishable in greyscale. It would thus greatly help the reader of the printed journal if these particular atoms could be labelled in Fig. 4. This can be done by the Editorial Office, or the authors may supply a revised figure - please advise] [The Abstract mentions an in-depth NMR study, but no details are given. Please provide this missing information.]