Structures of cefradine dihydrate and cefaclor dihydrate from DFT-D calculations

The crystal structure of cefradine dihydrate, C₁₆H₁₉N₃O₄S·2H₂O, is considered in the pharmaceutical sciences to be the epitome of an isolated-site hydrate. The structure from single-crystal X-ray data was described in 1976, but atomic coordinates were not published. The atomic coordinates are determined here by combining the information available from the published single-crystal data with a dispersion-corrected density functional theory (DFT-D) method that has been validated to reproduce mol­ecular crystal structures very accurately. Additional proof for the correctness of the structure comes from comparison with cefaclor dihydrate, C₁₅H₁₄ClN₃O₄S·2H₂O, which is isomorphous and for which more complete single-crystal data are available. H-atom positions have not previously been published for either compound. The DFT-D calculations confirm that both cefradine and cefaclor are present in the zwitterionic form in the two dihydrate structures. A potential ambiguity concerning the orientation of the cyclo­hexa­dienyl ring in cefradine dihydrate is also clarified, and on the basis of the calculated energies it is shown that disorder should not be expected at room temperature. The DFT-D methods can be applied to recover full structural data in cases where only partial information is available, and where it may not be possible or desirable to obtain new experimental data.

Computing details

For both compounds, program(s) used to solve structure: energy-minimized DFT-D calculation.

(I) Cefradine dihydrate

Crystal data

C16H19N3O4S·2H2O	β = 102°
Mr = 385.44	V = 909.8 Å^3
Monoclinic, P21	Z = 2
Hall symbol: P 2yb	F(000) = 408.0
a = 10.72 Å	Dx = 1.407 Mg m^−3
b = 7.31 Å	T = 298 K
c = 11.87 Å

Data collection

h = →	l = →
k = →

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Biso*/Beq
S1	0.65520	0.60896	0.88510
O1	0.18867	0.34388	0.67668
O2	0.17755	0.65406	0.66345
O3	0.40448	0.64013	0.52164
O4	0.84801	0.57203	0.55660
N1	0.46268	0.50979	0.70975
N2	0.69951	0.71373	0.63967
N3	0.97769	0.86387	0.52822
C1	0.39567	0.53033	0.88883
C2	0.53050	0.53250	0.95841
C3	0.59860	0.47629	0.75639
C4	0.36613	0.51597	0.77302
C5	0.23249	0.50477	0.69957
C6	0.47952	0.57887	0.60643
C7	0.62509	0.55000	0.63956
C8	0.80483	0.71325	0.59400
C9	0.86931	0.89919	0.58731
C10	0.91259	0.99824	0.69963
C11	0.88553	1.17661	0.70515
C12	0.93129	1.29267	0.80901
C13	1.02030	1.19352	0.90319
C14	1.04580	1.01520	0.89885
C15	0.98926	0.89413	0.79952
C16	0.29440	0.54678	0.95838
H2	0.66201	0.83531	0.66714
H2A	0.53807	0.62555	1.03245
H2B	0.55576	0.39666	0.99686
H3	0.61798	0.32934	0.77090
H3A	0.93434	0.82988	0.44142
H3B	1.04004	0.76222	0.57051
H3C	1.03226	0.98026	0.52147
H7	0.66025	0.44347	0.58885
H9	0.80130	0.98674	0.52894
H11	0.82885	1.24441	0.62947
H12A	0.97815	1.41572	0.78274
H12B	0.84899	1.34785	0.84138
H13	1.06653	1.27411	0.97762
H14	1.11335	0.95240	0.96975
H15A	1.06574	0.81548	0.77205
H15B	0.92833	0.78783	0.82746
H16A	0.28552	0.69062	0.98423
H16B	0.31906	0.46642	1.03836
H16C	0.20071	0.50157	0.91026
O5	0.57022	0.02320	0.69579
H5A	0.48075	0.00878	0.70770
H5B	0.56336	0.08220	0.61975
O6	0.32842	−0.00029	0.73674
H6A	0.27575	0.11082	0.71600
H6B	0.27579	−0.10778	0.70734

Geometric parameters (Å, º)

S1—C2	1.8277	C7—H7	1.0978
S1—C3	1.8048	C8—C9	1.5344
O1—C5	1.2746	C9—C10	1.5033
O2—C5	1.2715	C9—H9	1.1005
O3—C6	1.2345	C10—C11	1.3403
O4—C8	1.2500	C10—C15	1.5018
N1—C3	1.4677	C11—C12	1.4929
N1—C4	1.4002	C11—H11	1.0931
N1—C6	1.3725	C12—C13	1.4973
N2—C7	1.4382	C12—H12A	1.1063
N2—C8	1.3502	C12—H12B	1.1089
N2—H2	1.0547	C13—C14	1.3351
N3—C9	1.4991	C13—H13	1.0914
N3—H3A	1.0678	C14—C15	1.4979
N3—H3B	1.0542	C14—H14	1.0909
N3—H3C	1.0450	C15—H15A	1.1046
C1—C2	1.5083	C15—H15B	1.1093
C1—C4	1.3491	C16—H16A	1.1050
C1—C16	1.4991	C16—H16B	1.1009
C2—H2A	1.1009	C16—H16C	1.0980
C2—H2B	1.1028	O5—H5A	1.0037
C3—C7	1.5678	O5—H5B	0.9892
C3—H3	1.1008	O6—H6A	0.9906
C4—C5	1.5165	O6—H6B	0.9877
C6—C7	1.5425
C2—S1—C3	95.06	N2—C7—H7	109.71
C3—N1—C4	126.13	N2—C8—O4	123.16
C3—N1—C6	95.38	N2—C8—C9	116.22
C4—N1—C6	135.78	O4—C8—C9	120.61
C7—N2—C8	120.49	C8—C9—N3	105.84
C7—N2—H2	117.03	C8—C9—C10	116.11
C8—N2—H2	122.05	C8—C9—H9	107.53
C9—N3—H3A	105.51	N3—C9—C10	111.81
C9—N3—H3B	112.02	N3—C9—H9	106.38
C9—N3—H3C	113.35	C10—C9—H9	108.67
H3A—N3—H3B	113.65	C9—C10—C11	118.81
H3A—N3—H3C	104.70	C9—C10—C15	118.26
H3B—N3—H3C	107.50	C11—C10—C15	122.88
C2—C1—C4	123.64	C10—C11—C12	123.77
C2—C1—C16	114.76	C10—C11—H11	119.33
C4—C1—C16	121.60	C12—C11—H11	116.88
C1—C2—S1	117.06	C11—C12—C13	112.98
C1—C2—H2A	110.29	C11—C12—H12A	108.65
C1—C2—H2B	110.00	C11—C12—H12B	110.14
S1—C2—H2A	104.56	C13—C12—H12A	110.35
S1—C2—H2B	109.36	C13—C12—H12B	110.29
H2A—C2—H2B	104.77	H12A—C12—H12B	104.04
N1—C3—S1	111.24	C12—C13—C14	123.20
N1—C3—C7	87.55	C12—C13—H13	117.05
N1—C3—H3	111.23	C14—C13—H13	119.74
S1—C3—C7	118.25	C13—C14—C15	123.69
S1—C3—H3	111.88	C13—C14—H14	119.31
C7—C3—H3	114.25	C15—C14—H14	116.98
C1—C4—N1	120.40	C14—C15—C10	112.80
C1—C4—C5	125.70	C14—C15—H15A	109.64
N1—C4—C5	113.90	C14—C15—H15B	110.22
C4—C5—O2	117.61	C10—C15—H15A	110.40
C4—C5—O1	115.76	C10—C15—H15B	109.35
O2—C5—O1	126.57	H15A—C15—H15B	104.06
N1—C6—O3	132.65	C1—C16—H16A	110.08
N1—C6—C7	92.06	C1—C16—H16B	111.14
O3—C6—C7	135.29	C1—C16—H16C	112.22
C6—C7—C3	85.00	H16A—C16—H16B	106.70
C6—C7—N2	114.71	H16A—C16—H16C	107.97
C6—C7—H7	113.69	H16B—C16—H16C	108.52
C3—C7—N2	119.19	H5A—O5—H5B	106.40
C3—C7—H7	112.78	H6A—O6—H6B	108.07

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O5—H5A···O6	1.00	1.74	2.740	175.0
O5—H5B···O3^i	0.99	1.83	2.785	160.8
O6—H6A···O1	0.99	1.95	2.939	174.0
O6—H6B···O2^ii	0.99	2.05	3.028	173.3
N2—H2···O5^iii	1.05	1.76	2.805	168.5
N3—H3A···O1^iv	1.07	1.72	2.704	151.7
N3—H3B···O2^v	1.05	1.83	2.844	160.8
N3—H3C···O4^vi	1.05	1.86	2.757	142.0

Symmetry codes: (i) −x+1, y−1/2, −z+1; (ii) x, y−1, z; (iii) x, y+1, z; (iv) −x+1, y+1/2, −z+1; (v) x+1, y, z; (vi) −x+2, y+1/2, −z+1.

(II) Cefaclor dihydrate

Crystal data

C15H14ClN3O4S·2H2O	β = 105.0 (2)°
Mr = 403.85	V = 911.3 (9) Å^3
Monoclinic, P21	Z = 2
Hall symbol: P 2yb	F(000) = 420.0
a = 10.626 (3) Å	Dx = 1.471 Mg m^−3
b = 7.1288 (9) Å	T = 298 K
c = 12.455 (3) Å

Data collection

h = →	l = →
k = →

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Biso*/Beq
Cl1	0.29840	0.52390	0.94750
S1	0.66450	0.63120	0.86690
O1	0.19370	0.33700	0.66410
O2	0.18070	0.64900	0.66450
O3	0.40110	0.64600	0.52510
O4	0.85130	0.57470	0.56010
N1	0.47090	0.49700	0.70170
N2	0.70420	0.71800	0.63340
N3	0.98390	0.87300	0.53650
C1	0.41710	0.52600	0.87300
C2	0.55500	0.54400	0.94300
C3	0.61000	0.47700	0.74880
C4	0.37600	0.50800	0.76140
C5	0.23590	0.49700	0.69180
C6	0.48060	0.58000	0.60270
C7	0.63000	0.55000	0.63650
C8	0.81030	0.72100	0.59380
C9	0.87610	0.90300	0.59370
C10	0.92880	0.99600	0.70600
C11	0.89990	1.18200	0.71990
C12	0.95500	1.26800	0.82100
C13	1.03100	1.17200	0.90800
C14	1.06060	0.98100	0.89560
C15	1.00930	0.89200	0.79330
H2	0.66746	0.84066	0.66099
H2A	0.55943	0.64556	1.01040
H2B	0.58984	0.40972	0.98422
H3	0.63861	0.33049	0.76918
H3A	0.93706	0.83660	0.45265
H3B	1.04971	0.76904	0.57833
H3C	1.03735	0.99355	0.53092
H7	0.66238	0.43886	0.58872
H9	0.80656	1.00001	0.54005
H11	0.83915	1.26154	0.65096
H12	0.93390	1.41597	0.83113
H13	1.07239	1.24129	0.98728
H14	1.12428	0.90547	0.96472
H15	1.03300	0.74616	0.78086
O5	0.56990	0.03100	0.69070
H5A	0.48380	0.01313	0.70865
H5B	0.55204	0.09325	0.61786
O6	0.33560	0.00000	0.74760
H6A	0.28078	0.11104	0.71917
H6B	0.28200	−0.11230	0.72131

Geometric parameters (Å, º)

Cl1—C1	1.7487	C3—H3	1.0990
S1—C2	1.7915	C4—C5	1.5185
S1—C3	1.8073	C6—C7	1.5483
O1—C5	1.2414	C7—H7	1.0983
O2—C5	1.2372	C8—C9	1.4740
O3—C6	1.2027	C9—C10	1.5179
O4—C8	1.2443	C9—H9	1.1024
N1—C3	1.4493	C10—C11	1.3820
N1—C4	1.4014	C10—C15	1.4079
N1—C6	1.3953	C11—C12	1.3866
N2—C7	1.4399	C11—H11	1.0902
N2—C8	1.3426	C12—C13	1.3571
N2—H2	1.0510	C12—H12	1.0925
N3—C9	1.5126	C13—C14	1.4149
N3—H3A	1.0661	C13—H13	1.0898
N3—H3B	1.0588	C14—C15	1.4013
N3—H3C	1.0423	C14—H14	1.0897
C1—C2	1.5041	C15—H15	1.0902
C1—C4	1.3509	O5—H5A	1.0046
C2—H2A	1.1003	O5—H5B	0.9833
C2—H2B	1.1039	O6—H6A	0.9922
C3—C7	1.5576	O6—H6B	0.9879
C2—S1—C3	95.99	O3—C6—C7	136.89
C3—N1—C4	126.11	C6—C7—C3	85.51
C3—N1—C6	95.66	C6—C7—N2	114.07
C4—N1—C6	132.30	C6—C7—H7	113.28
C7—N2—C8	122.74	C3—C7—N2	120.32
C7—N2—H2	115.53	C3—C7—H7	112.35
C8—N2—H2	121.68	N2—C7—H7	109.57
C9—N3—H3A	106.10	N2—C8—O4	120.74
C9—N3—H3B	110.58	N2—C8—C9	117.25
C9—N3—H3C	114.02	O4—C8—C9	122.00
H3A—N3—H3B	113.15	C8—C9—N3	107.05
H3A—N3—H3C	105.05	C8—C9—C10	116.46
H3B—N3—H3C	107.94	C8—C9—H9	108.00
Cl1—C1—C2	114.92	N3—C9—C10	110.61
Cl1—C1—C4	117.36	N3—C9—H9	105.89
C2—C1—C4	127.70	C10—C9—H9	108.31
C1—C2—S1	113.06	C9—C10—C11	119.57
C1—C2—H2A	109.95	C9—C10—C15	119.15
C1—C2—H2B	110.78	C11—C10—C15	121.25
S1—C2—H2A	105.66	C10—C11—C12	118.86
S1—C2—H2B	111.19	C10—C11—H11	120.39
H2A—C2—H2B	105.83	C12—C11—H11	120.67
N1—C3—S1	110.36	C11—C12—C13	121.75
N1—C3—C7	88.03	C11—C12—H12	118.73
N1—C3—H3	112.28	C13—C12—H12	119.49
S1—C3—C7	115.99	C12—C13—C14	120.09
S1—C3—H3	112.26	C12—C13—H13	120.80
C7—C3—H3	115.53	C14—C13—H13	119.09
C1—C4—N1	117.76	C13—C14—C15	119.33
C1—C4—C5	126.90	C13—C14—H14	119.96
N1—C4—C5	115.34	C15—C14—H14	120.70
C4—C5—O2	115.89	C14—C15—C10	118.65
C4—C5—O1	115.87	C14—C15—H15	120.74
O2—C5—O1	128.09	C10—C15—H15	120.59
N1—C6—O3	132.76	H5A—O5—H5B	107.05
N1—C6—C7	90.36	H6A—O6—H6B	107.06

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O5—H5A···O6	1.00	1.77	2.768	174.9
O5—H5B···O3^i	0.98	2.00	2.902	150.6
O6—H6A···O1	0.99	1.90	2.884	173.5
O6—H6B···O2^ii	0.99	2.04	3.026	176.6
N2—H2···O5^iii	1.05	1.80	2.838	167.2
N3—H3A···O1^iv	1.07	1.73	2.726	153.1
N3—H3B···O2^v	1.06	1.75	2.782	164.9
N3—H3C···O4^vi	1.04	1.93	2.770	135.6

Symmetry codes: (i) −x+1, y−1/2, −z+1; (ii) x, y−1, z; (iii) x, y+1, z; (iv) −x+1, y+1/2, −z+1; (v) x+1, y, z; (vi) −x+2, y+1/2, −z+1.