Identification of Substituted Barbituric Acids by X-Ray DifFraction P. P. WILLIAMS Dominion laboratory, Wellington, New Zealand
b The x-ray diffraction patterns of 20 commonly used 5,5-disubstituted barbituric acids, crystallized from diethyl ether, have been obtained on a Geiger counter diffractometer. X-ray identification of barbituric acids isolated in toxicological examinations is practical, if the specimen preparation is standa rdized,
B
ARBITURIC acids are usually isolated
in the toxicological examination of tissues, as crystalline solids, and may therefore be identified from the x-ray diffraction pattern of the extract, provided the x-ray patterns of the pure compounds are available for cornparison. Previous authors (2, S, 6, 8) have published data for 20 compounds, and the patterns of 10 of them are to be found in the x-ray powder data file ( I ) . The results obtained in the present investigation of 20 barbituric acids show certain differences from those previously published. Therefore, it is proposed to list the x-ray patterns of twenty 5,5-disubstituted barbituric acids which have been crystallized by evaporation of an ethereal solution. METHODS
Nomenclature of the barbiturates is confusing, because of the variety of trade names that may be used for a single compound. The names used here are those used for the acids by Chemical Abstracts since 1951. Table I lists them together vvith synonyms and the substituents on the barbituric acid ring. The barbituric acids were isolated from commercial samples obtained from reputable drug houses. They were purified by repeated crystallization from aqueous alcohol, or in some cases from water, until a constant melting point ryas obtained which agreed with the published values. Crystals for examination were obtained by separately dissolving the compounds in ether, and allowing the solutions to evaporate to dryness at room temperature. Thus, the x-ray patterns obtained should be directly applicable to toxicological samples (9). The diffraction patterns were obtained on a Norelco wide-angle Geiger diffractometer, using filtered copper radiation, and a rotating flat specimen holder. Interplanar spacing was calculated for X(CuKcu) = 1.5418A. 140
ANALYTICAL CHEMISTRY
Table 1. Names of Barbituric Acids Studied Name Recommended by Chemical Abstracts Synonyms Substituents Amobarbital Amytal, Amylobarbitone 5-Ethyl, 5-isoamyl Aprobarbital Allonal, Allypropymal, 5-.411yl, 5-isopropyl Alurate, Numal Barbital Diemal, Verona1 5,5-Diethyl Butabarbital Butisol 5-Ethyl, 5-see-butyl Butethal Neonal, Soneryl 5-Ethy1, 5-butyl Cyclobarbital Hexemal, Phanadorm 5-Ethyl, 5-Az-cyclohexenyl Cyclopal 5-Allyl, 5-cyclopentenyl Dial Allobarbitone, Diallymal 5,5-Diallyl Hexobarbital Cyclonal, Enhexymal, Evipal A’-Methyl, 5-methyl, 5-cyclohexenyl Kemithal 5-Ally1, 5-Az-cyclohexenyl, thiobarbituric acid Mephobarbital Mebaral, Phemitone, Prominal A;-hlethyl, 5-ethyl, &phenyl Nostal Noctal 5-Isopropyl, 5-@-bromallyl Pentobarbital 5-Ethyl, 5-a-methyl butyl Phenobarbital Fenemal, Gardenal, Luminal 5-Ethyl, 5-phenyl Probarbital Ipral 5-Ethyl, 5-isopropyl Rutonal 5-Methyl, 5-phen 1 Sandoptal 5-Allyl, 5-isobutyr Secobarbital Seconal 5-Ally1, 5- methyl butyl Thiamylal 5-Allyl, 5-CY-methyl butyl thiobarbituric acid Thiopental Intraval, Pentothal 5-Ethy1, 5-0-methyl butyl thiobarbituric acid
DISCUSSION OF RESULTS
The results obtained in this investigation are presented in Table 11. The method used in this work presents the diffraction pattern in the form of a trace on a strip chart, from which d spacings can be calculated from the ordinate (which is a n angular measurement), while the abscissa gives intensities directly. The accuracy of the intensities depends, to a certain extent, on the mounting of the sample, and on the instrumental recording conditions. In this work, accuracy is estimated to be &lo% of the reported value. Comparison of the diffraction patterns is greatly facilitated if the reference data are complete-Le., if low intensity lines are included-because it is often only by comparison of such lines that the purity of the unknown can be estimated. Further, it is essential that the reference data also include line intensities. Relative intensities measured on a diffractometer record do not always compare well with intensities estimated from a photographic record, and this is most apparent when photographic intensities described as “weak,” “strong,” etc., are converted to percentage relative intensities.
The x-ray powder data file (1) contains patterns of Aprobarbital (three forms), Barbital (four forms), Butethal, Cyclobarbital, Dial, Hexobarbital, Pentobarbital, and Phenobarbital (five forms) obtained by Huang (2, S, 6) and of Amobarbital, Phenobarbital, and Secobarbital, obtained from the Eli Lilly and Co. laboratories. I n many cases, these data are in substantial agreement with those found in this investigation. Crystallization from ether has been found to produce modification I1 of Barbital, together with small amounts of modifications I and IV in reproducible proportions. An extra line has been found in Phenobarbital (modification 11) a t 23.6 A. which may have been outside the recordable range of Huang’s 19-cm. camera. However, the patterns recorded for Amobarbital, Butethal, and Pentobarbital do not agree at all with those in the x-ray powder data file. These disagreements are probably due to polymorphism, but the patterns reported in Table I1 should be of value to toxicologists. Crystallization from ether produces reproducible patterns for all the compounds studied, except Aprobarbital. The pattern given here
Table II. X-Ray Diffraction Patterns of Barbituric Acids
Amobarbital d , A. 1/11 10.8 100 10.3 i3 7.56 38 7.10 75 6.13 29 2 5.83 5.52 45 93 5.39 6 5.18 4.92 30 4.72 24 4.48 32 42 4.04 62 3.82 3.76 3 3.62 3.59 3 6 3.38 2 3.28 3.21 9 I 3.13 3.01 7 2.96 4 2.90 10 2.802 10 2.712 13 2.685 11 2.585 8 6 2.508 2 2.392 7 2.344 2.292 3 2 , 226 3 2.12" 1 2.100 1 1 2.067 2.018 2 2 1,957 1 1.931 2 1,895
--
-
I
Aprobarhital 11.2 100 8.68 44 6.80 I 27 6.61 53 6.53 I1 28 6.20 I 6 5.98 10 5.86 10 5.61 100 5.20 36 5.14 I1 32 5.02 i4 4.8i 9 4.70 45 4.55 I 4 4.33 11 4.05 41 4.01 11 3 3.85 3 3.73 61 3.67 1,II 3 3.56 I1 13 3.45 I1 3 3.38 8 3.28 16 3.26 I,I1 23 3.21 8 8 3.13 I 3.10 38 5 3.03 2.97 6 5 2.96 I1 2.88 5 2.85511 4 2.800 30
~-~
Aprobarbital (cont.) d, A. 1/11 2 767 5 7 2.690 3 2.608 5 2.535 3 2.410 2.355 3 2 2.338 2.318 I 2 5 2.237 2 2.189 I 2.163 3 4 2.145 3 1.930 2 1.900 7 1.870 Barbital 13.0 1 11.2 1 7.8 8 7.1 6.35 5.74' 11 5.30 100 5.12 5 2 4.91 4.71 1 1 4.50 4.23 2 3.86 3 4 3.67 3.54 15 2 3.37 2 3.34 3.19 1 3.09 3 4 3.04 4 2.97 18 2.855 1 2.690 10 2.660 3 2.550 2.522 3 1 2.433 1 2.346 2.275 1 2.228 4 1 1.950 1.931 1 2 1.892 1.810 1 1 .i45 1 1.677 1 c
b
Rutonal 15.2 13.6 12.1 7.63 6.28 5.76 5.56 5,21 5 04 4 70 4 35 4 04 3 96 3 77 3 65 3 42 3 34 3 20 3 06 3 00 2 81 2 605
100 1 1
15 1 2 2 8 9 1 1 4 2
9 16 1
2 1 4 3 5 1
Rutanol (cont.) d , A. 1/11 2.500 1 2.430 1 2.380
