Infra-red spectroscopic identification of non-barbiturate sedatives

Sections

I. Introduction
II. Experimental
III. Discussion
Conclusion and summary

Details

Author: P. N NATARAJAN
Pages: 39 to 42
Creation Date: 1972/01/01

Infra-red spectroscopic identification of non-barbiturate sedatives

P. N NATARAJAN School of Pharmacy, University of Singapore, Singapore 3

I. Introduction

Methylparafynol ( [ 1] to 6), ethchlorvynol ( [ 7] to 13), centalum ( [ 14] , 15), ethinamate ( [ 16] to 21), glutethimide ( [ 22 ] to 37), methprylon ( [ 38] to 48), pyrithyldione ( [ 49] to 51) and methaqualone ( [ 52] to 61) are extensively used as tranquillisers, sedatives and hypnotics. Their central depressant action is less than that of the barbiturates and hence larger and more frequent doses are required to produce sedation. Further, the margin between the therapeutic dose of these and the dose which is liable to cause withdrawal symptoms is less. Addiction, arising out of long term therapy, as well as fatal poisoning, often due to deliberate ingestion for suicidal purposes, are common problems in the use of these drugs. Consequently forensic and toxicological laboratories are faced with problems in their identification in small quantities. The method reported in the literature employing nuclear magnetic resonance spectroscopy ( [ 62] ) for the identification of these drugs suffers from the disadvantage that substantial amounts of materials are required. The infra-red spectroscopic method described in this paper provides a satisfactory and rapid method for the identification of these compounds when comparatively small quantities of material are available.

Of the eight psychotropic substances discussed in the present article, pyrithyldione, methylparafynol and centalum are not included in the schedules of the Convention on Psychotropic Substances, adopted in Vienna in February 1971. However, pyrithyldion bears a structural resemblance to methylprylon as do centalum and methylparafynol to ethchlorvynol; both methylprylon and ethchlorvynol being included in Schedule IV of the Convention. Neither the psychotropic activity, nor the tendency to engender dependence, of these three drugs differs to any significant degree from their counterparts. Considering that these compounds could come to be included in future revisions of the Schedule, the spectral details leading to their identification are included in the present discussion.

II. Experimental

The infra-red spectrograms presented here were recorded on a Jasco model IR-S double beam spec- trophotometer with sodium chloride optics. The reproducibility is 0.5 cm -1 and the resolution is 1 cm at 1000 cm -1. All spectra were calibrated with standard polystyrene film and the necessary corrections have been made. The intensities of the absorption peaks are described relative to all other bands in a given spectrum.

The sample preparation technique can have profound effect on the spectra of a compound ( [ 63] ). Changes in the spectra of a compound have been noted due to either grinding with potassium bromide ( [ 64] , [ 65] ) or conversion of a crystalline form into an amorphous form or into a second crystalline form (66). To avoid such discrepancies, solution spectra have been taken. The sample used was a 1% chloroform solution in a 0.025 cm sodium chloride cell. It is pertinent to emphasize that samples for infrared spectroscopic comparison must be prepared under identical conditions.

III. Discussion

The eight compounds described could be classified from a chemical point of view into two groups, one (see table, compds 1-3) containing a tertiary carbinol function and the other (see table, compds 4-8) containing an open chain amide or cyclic imide structure. The major absorption peaks taken into consideration for identifying the compounds are those mainly associated with these functions. An attempt has been made to assign most of the bands to their characteristic vibrational modes ( [ 67] to 70).

Methylparafynol, ethchlorvynol and centalum can be identified by the O-H stretching vibrations occurring in all these compounds as a medium peak between 3760-3740 cm -1 and as a strong peak at 3400 cm -1. Methylparafynol could be further distinguished from centalum and ethchlorvynol by the complete absence of any strong peak in the region of 1700-1600 cm -1 and the appearance of two strong C-H out-of-plane deformation bands at 988 cm -1 and 905 cm -1. Ethchlorvynol exhibits a strong vinyl stretching absorption at 1625 cm -1 and four C-H out-of-plane deformation frequencies of the trans vinyl structure in the region of 990-928 cm -1. The two absorption frequencies appearing as a very strong cleft band at 939 cm -1 and 928 cm -1 are characteristic.

Infra-red absorption patterns of non-barbiturate sedatives

 

Absorption peaks in cm -1

Generic name

4000-3000

2999-2000

1800-1700

1699-1600

1599-1500

1499-1400

1399-1300

1299-1200

1199-1100

1099-1000

999-900

899-800

1. Methylparafynol
3760m 2980m         1380m   1190m   988s 885sh
  3400s 2940s
-
-
-
1455m 1345m
-
1155m
-
   
    2880m         1320m   1125m   905vs  
                         
2. Ethchlorvynol
3760m 2970m        
1320-
1282m 1190s   990s  
  3400s 2920m
-
1625s
-
1460m 1311m    
-
968m
-
  3010w          
cleft
  1120m   939vs  
             
band
      928vs  
                         
3. Centalum
3740s         1495w 1375m  
1185-
1080s    
  3400s
-
-
  1510w 1445m
1342-
-
1178m  
925-
-
  3010m     1608s     1330mb  
cleft
1030s 915s  
                 
band
1012m
cleft
 
                     
band
 
4. Ethinamate
3600s   1735vs   1585vs   1360vs 1290w 1190s 1095m   890w
  3480s 2920s  
-
  1442m 1340vs     1045vs 958w 840w
  3380s 2860m             1140m 1020vs 910m  
    2960m       1495w 1390m   1165s      
                         
5. Glutethimide
                       
  3450m   1710vs  
-
1442m 1345s
-
 
-
-
-
        1605m     1332s          
                         
6. Methylprylon
3800w 2960m   1660vs   1482m 1382m   1185s 1070m    
  3480m 2900m 1720s  
-
1452s 1360s
-
      852m
        1608m     1328w   1120w 1020w 902w  
              1300w     1000w    
                         
7. Pyrithyldione
3820w     1655vsb     1385m 1290w        
  3470m 2990m 1710vs 1635vsb
-
1455s 1360s  
-
1055s    
  3280mb 2960m         1325m     1025w 915w
-
                         
8. Methaqualone
  2980w   1685vs 1575m 1490w 1382m 1282w
1195-
  992w 865w
     
-
1605vs   1465m 1340s 1265m 1185mb      
            1455sh 1322s   1125m 1010w    
            1425w     1100m      

b = broad; m = medium; s = strong; vs = very strong; sh = shoulder; w = weak.

Centalum shows a strong atomatic C = C skeletal inplane stretching vibration at 1608 cm -1 besides a strong cleft band at 915 -925 cm -1 due to a C-H out-of-plane deformation mode. The C-O stretching vibrations of the tertiary and secondary unsaturated alcoholic functions in this compound result in the two strong bands at 1080 cm -1 and 1030 cm -1.

The strong to very strong C = O stretching absorption frequency of primary and secondary amides, often referred to as amide I band, occurring between 1735-1710 cm -1 is a general feature of ethinamate, glutethimide, methylprylon and pyrithyldione. In methaqualone which is a cyclic tertiary amide, this band is shifted to a lower frequency of 1685 cm -1. This coupled with the absence of N-H stretching vibrations in the region of 3500-3200 cm-1 and the occurrence of a very strong aromatic C = C skeletal in-plane stretching vibration at 1605 cm -1 helps to identify this compound. Ethinamate, being a primary amide shows two strong N-H stretching absorption bands at 3480 cm [ 1] and 3380 cm -1. The amide I band in this compound occurs at 1735 cm -1. The outstanding feature in the spectrum of ethinamate is however a pair of very strong bands at 1045 cm -1 and 1020 cm -1 both due to the C-O stretching modes assigned to the C-O link of the cyclohexanol residue. Glutethimide shows the N-H stretching frequency as a medium band at 3450 cm -1 and the aromatic C = C skeletal in-plane stretching vibration at 1605 cm -1. The absence of any significant bands between 1000-800 cm -1 and the appearance of a strong non specific absorption band at 1165 cm -1 serve as further useful characteristics for the identification of this compound.

The structures of methylprylon and pyrithyldione are very similar except for a methyl function in position five of methylprylon. Consequently the exact position of the absorption bands arising from the common functional groups in these compounds becomes important. In the spectra of methylprylon, the N-H stretching frequency occurs as a medium absorption at 3480 cm -1 the amide I band occurs as a strong peak at 1720 cm -1 and the C-O stretching vibration of the carbonyl function is seen as a single very strong band at 1660 cm -1. The strong band at 1185 cm -1 exhibited by methylprylon which does not occur in the spectra of pyrithyldione is an important point of difference. Pyrithyldione, in its spectra shows the N-H stretching frequency as a medium band at 3470 cm -1 and the amide I band as a very strong absorption at 1710 cm -1. However, in contrast to methprylon, the C-O stretching vibration of the carbonyl function in pyrithyldione appears as two very strong broad bands at 1655 cm -1 and 1635 cm -1, which together with the strong band occurring at 1290 cm -1 serve as distinguishing features of this compound.

Conclusion and summary

The infra-red spectrograms of eight frequently used non-barbiturate sedatives have been discussed. Both from the table of the absorption patterns and the spectra of the compounds, it is apparent that they can be easily distinguished and identified. The advantage of this method lies in the small quantities of the samples required for analyses, which is often the case in forensic and toxicological investigations. The extensive references cited deal with the syntheses, clinical reports, toxic side effects, reported cases of addiction, withdrawal symptoms, deaths due to over dosage and attempted suicides of these compounds.

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