The barbiturates present a formidable group of compounds to analyse from small samples and to identify specifically from one another. The infra-red absorption spectra are their most fundamental characteristic physical property in the solid state. Recordings of the individual infra-red absorption spectra of the barbiturates provide the basis of an excellent reference file. If this reference file is established on a quantitative basis, then critical procedures for qualitative and quantitative analyses of these closely related compounds can be developed.
Author: James J. Manning, Kevin P. O’Brien
Pages: 25 to 34
Creation Date: 1958/01/01
The barbiturates present a formidable group of compounds to analyse from small samples and to identify specifically from one another. The infra-red absorption spectra are their most fundamental characteristic physical property in the solid state. Recordings of the individual infra-red absorption spectra of the barbiturates provide the basis of an excellent reference file. If this reference file is established on a quantitative basis, then critical procedures for qualitative and quantitative analyses of these closely related compounds can be developed.
The history, chemical structure and synthesis of the barbituric acids have recently been described by Levi [1] in the Bulletin on Narcotics.
Instrumental procedures, including ultra-violet and infrared absorption analytical methods have been developed for the analysis of barbiturates [2] , along with procedures including colour reactions, titrimetric procedures, microcrystal tests, paper chromatography and complex derivatives [3] , [4] .
Experimental
The spectra were recorded on a Perkin-Elmer model 21, double-beam, optical null infra-red spectrophotometer. The samples contain 0.002 g of barbiturate thoroughly powdered and mixed with 0.998 g of spectral pure potassium bromide. From the. 1.000-g mixtures 0.300 g were weighed and then pressed into 13-mm discs, approximately 1 mm thick, in a KBr die under 20,000 lb./sq.in, pressure. These discs were mounted directly in the light path of the infra-red spectrophotometer by means of a micro-sample adapter. Sampling equipment and techniques are described in detail in the references [5] , [6] cited in the bibliography.
Identification of a Barbiturate by its Characteristic Infra-red Spectrum
The general empirical method of identifying an unknown substance by directly comparing its characteristic infra-red spectrum with the infra-red spectra of known compounds was described by the author in a previous contribution on narcotics to the Bulletin on Narcotics[7] . In the present article, a short summary is presented of the method by which an individual barbiturate may be identified by a detailed consideration of the individual group frequencies. The infra-red spectrum is a unique and characteristic physical property of that substance-based upon the fundamental functional groupings in the molecule. A study of the prominent features of the spectrumwill often yield sufficient structural information to identify the nature of the unknown barbiturate.
The infra-red spectra of fourteen of the most important barbiturates were recorded as described above and illustrated in figures 1 to 14. A graphic summary of the prominent features of these spectra is shown in figure 15. The intensity of absorbence is represented by the height of the lines at the respective frequency or wavelength.
An examination of the resultant diagram shows all the compounds to have a band about 2.90 and a strong band at 3.10 to 3.15. According to Bellamy [8] , infra-red spectra of complex molecules, such as cyclic lactams in the solid state (KBr pressed bromide samples fit this description) show strongly a band at about 3.15 (NH hydrogen bonded) and more weakly free NH at 2.92. These cyclic lactams bear a strong resemblance to the barbiturates, the grouping (CO-NH-CO) is associated with a single NH frequency at about 3.13. Secondary amides show a band at about 2.9, displaced to about 3.1 in the solid state. There seems scarcely any doubt that the 3.1 band in these compounds is hydrogen bonded NH.
Some, but not all of these compounds show a strong band or bands at about 6.4. The "amide II" bands in secondary amides (which may be NH bending frequencies) occur from about 6.37 to 6.60 in solids. In nearly all these compounds, there is a feeble band at about 6.5 - 6.6, if the strong bands at about 6.4 are absent. Possibly the whole group are "amide II" bands, although there is no apparent explanation of why they should be so much stronger in some compounds than in others. The strong bands at about 6.4 are present when the di-alkyl substituted C-atom carries propyl or butyl groupings such as in
Why their presence on this carbon atom should influence the "amide II" vibrations, if the latter is an NH bending vibration, is difficult to explain.
A mixture of CH stretching frequencies, as they occur in CH 2 and CH 3 groups of relative intensities, governed by the number of CH 2 and CH 3 groups is to be expected in these compounds.
Figures 1 to 3
Figures 4 to 6
Figures 7 and 8
Figures 9 and 10
Figures 11 and 12
Fig 13 and 14
The barbiturates have saturated alkyl groups on the Carbon atom designated above. The group (-CH 2-CH 3), for example, would have four CH bands at about
3.37 | 3.42 | 3.48 | 3.51 |
CH in CH 3 |
CH in CH 2 |
CH in CH 3 |
CH in CH 2 |
asymmetrical |
asymmetrical |
symmetrical |
symmetrical |
Actually the di-ethyl compound has four bands at
3.26 | 3.36 | 3.40 | 3.50 |
strong |
weak |
strong |
strong |
Perhaps more definite assignments could be made in the region if lithium flouride optics were employed, since the resolving power of the rock-salt optics is considerably lower. Nevertheless, the fluctuations of the relative intensities of the observed bands with the variations in the CH 2 and CH 3ratio in the substituents are of some value in these assignments.
In the case of the compounds containing the (=CH 2) group, the high frequency band to be expected is 3.23, which might overlap with the NH group at about 3.15.
There is a complicated group of bands in the region 6.8-7.0. For CH bending in CH 2, the band at 6.8 is the expected position. The band present in nearly all these compounds at about 7.0 is undoubtedly the asymmetrical bending of CH in CH 3.
The CH bending vibration of unsaturated methylene (HC=CH 2) seems to show more or less clearly in all these compounds containing this linkage at about 7.04. It is well marked in Dial and distinct from the corresponding vibration in (-CH 2-) at longer wavelength. The CH bending vibration shows as a shoulder on the long wavelength side of the 7.0 band in Lotusate, as a mere taft of the 7.0 band to long wavelengths in Seconal and distinct in Alurate.
The out-of-plane bending vibration of the CH group in the methylene of (-HC=CH 2) ,at about 10 to 10.15 shows in all barbiturates containing the linkage and the combination of bands at about 7.04 and 10.10 seems to be a pretty good criterion for the presence of that linkage in these compounds. Further confirmation of this grouping can be found in the (C=C) vibration from 6 to 6.15, which shows in all of these barbiturates containing that linkage.
Most of these barbiturates contain 3 bands in the (C=O) region between 5.8 and 6.0. Compounds containing the group (CO-NH-CO) are known to show two (C-O) bands, one from about 5.85 to 6.0. The barbiturates have two such groups (with one common C=O) and one would expect more bands. The barbiturate Pentothal, with only two (CO's) still has three bands in the (CO) region, although it is much more feeble than the other two.
The (S=C) linkage, present in Pentothal, is notoriously uncertain in infra-red spectra. Pentothal has a strong band at 8.55 = 1170 cm-1 which is much stronger than in any other barbiturate in this group. The usual frequency suggested for (C=S) linkage is from 1300 to 1400 cm-1. It might be at a lower frequency in Pentothal because of a tendency to resonance.
Beside this tendency to resonance there might also be a tautomerization which is suggested by the feeble band at 3.85, the accepted value for the SH linkage. This thio-barbi-turate moreover is the only barbiturate in this group with a band at this position.
The presence of the benzene ring in the compounds luminal and mebaral, which contain it, seems to be indicated by the characteristic frequencies for the (C=C) in plane vibrations near 6.25 and 6.65, the latter the stronger band.
Conclusion
From the short description above, the value of infra-red absorption spectra for identifying purposes is apparent. The various functional groupings in the barbiturates are easily recognized. A direct comparison of the unknown's spectrum with known barbiturate infra-red spectra will provide positive identification.
Acknowledgement
The author wishes to thank Dr. William West for his review of the spectra. He is indebted to Miss Helen Stern-glanz for the recording of these spectra; and to Mr. Alexander Thomas for the preparation of the graphic summary of them.
Appreciation and thanks are expressed by the author to the pharmaceutical companies for their generous samples
LEVI, Leo: Bulletin on Narcotics, Vol. IX, No. 1, 1957.
002PENPRASE & BILES: Jour. Am. Pharm. Assoc. Science Ed., 45, 585 (1956).
003ALLPORT: Colorimetric Analysis, Chapman Hall, Ltd., London, 1947.
004CASTLE & POE: Journ. Am. Chem. Soc., 66, P. 1440, 1944.
005SCHIEDT: Applied Spectroscopy, Vol. 7, No. 2, P. 75, 1953.
006HAUSDORFF: Applied Spectroscopy, Vol. 8, No. 3, P. 131, 1954.
007MANNING: Bulletin on Narcotics, Vol. VII, No. 1, P. 85, 1955.
008BELLAMY: The Inflated Spectra of Complex Molecules, Methuen, London, 1954.