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Vibrational spectra of barbituric acid derivatives in low-temperature matrices
Journal of Molecular Structure, 56 (1979) 29--39 © Elsevier Scientific Publishing Company, Amsterdam -- Printed in The Netherlands
VIBRATIONAL SPECTRA OF BARBITURIC ACID DERIVATIVES IN LOW-TEMPERATURE MATRICES Part 3 . 5 , 5 - D i e t h v l b a r b i t u r i c acid ( b a r b i t a l )
A. J. BARNES
Department of Chemistry and Applied Chemistry, University of Salford, Salford M5 4WT (Gt. Britain)
L. LE GALL and J. LAURANSAN Laboratoire de Thermodynamique Chimique, Universit$ de Bretagne Occidentale, 6 Avenue le Gorgeu, 29283 Brest Cedex (France) (Received 28 March 1979)
ABSTRACT Infrared and Raman spectra are reported for 5,5-diethyl barbituric acid (barbital or barbitone), and for its deuterated counterpart, in argon and nitrogen matrices at different concentrations. Infrared, far infrared and Raman spectra of the solid phase were also obtained. The data enabled a vibrational assignment to be made for both the monomeric form and the solid. The modes which are characteristic of barbiturates are discussed. INTRODUCTION T h e i n f r a r e d s p e c t r u m o f b a r b i t a l has b e e n r e p o r t e d b y a n u m b e r o f a u t h o r s [ 1 - - 3 ] , a n d t h e R a m a n s p e c t r u m has also b e e n ob~mned [ 4 ] . As ~or o t h e r b a r b i t u r i c acid derivatives, detailed i n t e r p r e t a t i o n o f t h e s p e c t r a has largely b e e n c o n f i n e d t o t h e N - - H a n d C=O s t r e t c h i n g m o d e s , a n d t h e r e is c o n t r o versy o v e r the a s s i g n m e n t o f t h e b a n d s in t h e c a r b o n y l s t r e t c h i n g region. Mesley [3] has carried o u t a s t u d y o f p o l y m o r p h i s m in t h e b a r b i t u r a t e s , and details i n f r a r e d s p e c t r a o f f o u r distinct f o r m s o f solid barbital. I n f r a r e d spect r o s c o p y has b e e n used to s t u d y m e t a l c o m p l e x e s o f b a r b i t a l [5] and t h e h y d r o g e n - b o n d e d c o m p l e x o f b a r b i t a l w i t h a d e n i n e derivatives [ 6 ] . Matrix isolation v i b r a t i o n a l s p e c t r o s c o p y has e n a b l e d v i b r a t i o n a l assignm e n t s to be m a d e f o r b a r b i t u r i c acid a n d its 1 - m e t h y l a n d 1, 3 - d i m e t h y l subs t i t u t e d derivatives [7, 8 ] . I t is o f i n t e r e s t t o see w h e t h e r t h e a s s i g n m e n t can be e x t e n d e d to t h e p h a r m a c e u t i c a l l y i m p o r t a n t 5 , 5 - d i s u b s t i t u t e d derivatives such as barbital. An i n t e r p r e t a t i o n o f the v i b r a t i o n a l s p e c t r a o f b a r b i t u r a t e s w o u l d be o f o b v i o u s value in using i n f r a r e d o r R a m a n s p e c t r o s c o p y to s t u d y t h e b i n d i n g o f t h e drugs t o c o m p o u n d s such as a d e n i n e derivatives.
30 EXPERIMENTAL
The experimental details are similar to those described in Part 1 [7]. The barbital was obtained from Merck, and the deuterated c o m p o u n d was prepared by exchange with D20. RESULTS
Infrared spectra of barbital in argon matrices were recorded after deposition
0
from samples of the solid held at temperatures of 66°C, 77°C, 90°C and 100°C {the melting point of barbital is 190°C). Infrared spectra were also recorded of barbital in nitrogen matrices, and of barbital in argon matrices doped with 1% nitrogen. A spectrum of pure solid barbital was obtained by deposition at 20 K, annealing the solid at room temperature overnight, and then recooling to 20 K. Infrared spectra of the solid in a CsBr disc and far infrared spectra in a vaseline mull were also recorded. Spectra obtained in the N--H stretching region are compared in Fig. 1 (note that the quantity of barbital deposited differed from one sample to another). Deposition from the solid held at 66°C gave virtually only monomeric barbital, while deposition from the solid held at 100°C gave a mixture of m o n o m e r and dimer. A Raman spectrum of barbital in an argon matrix was recorded after deposition from a sample held at 75°C, and the Raman spectrum o f the pure solid was also recorded. The low temperature Raman spectrum of the solid showed evidence of polymorphism, splitting of m a n y bands being observed. Infrared spectra of 1,3-dideutero-5,5-diethyl barbituric acid (d-barbital) in argon matrices were recorded after deposition from samples of the solid held at temperatures in the range 66--105°C, and a spectrum of the pure solid was also obtained at 20 K. Raman spectra were recorded in an argon matrix, after deposition from a sample of the solid held at 75°C, and of the pure solid at 20 K. The spectra of barbital and d-barbital in the region 1500--400 cm -1 are compared in Fig. 2. DISCUSSION
According to the X-ray crystal structure determination [ 9], the ring in barbituric acid is significantly distorted from planarity, in such a way that the methylene part of the ring has a boat-shaped configuration. Assuming that the
31
3600
2600 ~, (crn-')
Fig. 1. Infrared spectra of the N--H stretching region of barbital (deposited from the solid held at different temperatures 0°C) in argon matrices and in the solid phase at 20 K.
isolated barbital molecule has a similar structure, it m a y retain the s y m m e t r y of barbituric acid, i.e. Cs. The 69 normal modes of vibration, of which 36 are associated with internal vibrations of the ethyl groups, then divide into 39 A' and 30 A" modes. Craven et al. [10] have reported crystal structures of three forms of solid barbital: barbital I has a structure identical to that of solid barbituric acid, i.e. the molecules are linked through the carbonyls in the 2 and 4 positions, barbital II has the molecules linked through the carbonyls in the 4 and 6 positions while barbital IV has the molecules linked by two hydrogen bonds to the carbonyl in the 4 position. In the dimer and in forms I and IV of the solid phase the plane of s y m m e t r y in the barbital m o n o m e r is lost. 4000--1800
c m -1 r e g i o n
Twelve modes are expected in this region: two NH(ND) stretching vibrations and ten CH stretching modes associated with the ethyl groups. Barbital gives only one band in the NH stretching region, whereas d-barbital has several weak bands close to the principal N--D stretching absorption. One of these may be
32
Ba rbi ta I
I
I
I
I
I
I
J
I
I
I
L
[
I
[
D-Barbital
V I I400
I 1200
I
I
I
1000
800
600
400
(cm -t )
Fig. 2. Infrared spectra of the 1500--400 cm -1 region of barbital and deuterated barbital (deposited from the solids held at 66°C) in argon matrices at 20 K.
t h e s e c o n d N - - D s t r e t c h i n g m o d e . T h e e f f e c t o f association o n t h e N - - H s t r e t c h i n g m o d e s is similar to t h a t f o u n d f o r b a r b i t u r i c acid. 1800--1600
c m -~ region
T h r e e c a r b o n y l s t r e t c h i n g m o d e s are e x p e c t e d in this region, w h o s e assignm e n t has b e e n t h e s u b j e c t o f c o n t r o v e r s y . In an a r g o n m a t r i x , t h e highest freq u e n c y b a n d ( 1 7 7 6 c m -~) is relatively w e a k in t h e infrared b u t intense in t h e R a m a n s p e c t r u m , while the l o w e r f r e q u e n c y b a n d s ( 1 7 5 7 a n d 1 7 2 6 c m -1) are intense in t h e i n f r a r e d b u t w e a k in t h e R a m a n s p e c t r u m (Fig. 3). This is
33
!
:-J (
[a)
_2_
I
i
]
!
1800 1700 1600 1800 1700 16001800 ~, ( cm -r)
I
t
(d)
L<
1700 1600 1800 1700 1600
Fig. 3. Carbonyl stretching region of barbital. A, IR spectrum in argon matrix; B, Raman spectrum in argon matrix; C, IR spectrum in solid phase (20 K); D, Raman spectrum in solid phase (room temperature).
analogous to the results for barbituric acid and its N-methyl substituted derivatives [7, 8]. Thus the highest frequency band is assigned to the 4,6-C=O symmetric stretch, the middle band to the 4,6-C=O antisymmetric stretch and the lowest frequency band to the 2-C=O stretch. Percy and Rodgers [11] arrived at the same assignment from infrared spectra of barbiturate complexes. The solid spectrum was complicated by polymorphism: two forms of the solid were found, each with two bands in the infrared or Raman spectrum of this region, at ca. 1760 and 1700 cm -1 or at ca. 1730 and 1690 cm -' (the latter is probably barbital I in view o f the similarity of the frequencies to those of BA). The higher frequency band in either form is the more intense in the Raman spectrum, and is clearly the 4,6-C=O symmetric stretch, while the lower frequency band is the more intense in the infrared spectrum and contains the other two carbonyl stretching modes. Other barbiturates apparently have the 4,6-C=O symmetric stretch near 1737 cm -1 [4]. 1600--1150
c m -1
region
In this region, barbital and d-barbital should show four ring C--N stretches plus twelve m e t h y l and methylene deformation modes associated with the ethyl groups. Additionally barbital should have two N--H in-plane bending modes. The C--N stretching modes are readily identified by comparison with BA (barbituric acid) and DBA [8], and the N--H in-plane bending modes appear in an argon matrix as a band at 1301 cm-' with a high frequency shoulder (Fig. 4). Unlike BA or MBA (1-methyl barbituric acid) there seems
34
©
r
8 : 66°C
L
I
I
[500
1400
1500
I
I
90%
E
12001500 1400
I 1500
L
IO0°C
I
t20015001400
I 1500
I
Pore
I
E
1 2 0 0 1 5 0 0 1400
I
I
1500
[200
v [cm -q )
Fig. 4. Infrared spectra of the 1500--1200 cm-1 region of barbital (deposited from the solid held at different temperatures 0°C) in argon matrices and in the solid phase at 20 K. to be no interaction with the overtones of the N--H out-of-plane bending modes, and only a small shift was observed between the argon and nitrogen matrix frequencies. The modes associated with the ethyl groups all give relatively weak absorptions and can only be assigned tentatively. 1 1 5 0 - - 8 0 0 c m -~ region
In this region two ring C--C stretches plus four m e t h y l rocking modes and fo ur C--C stretches associated with the ethyl groups are expected for both barbital and d-barbital. T he deuterated c o m p o u n d should show additionally the two N--D in-plane bending modes. The ring C--C stretching modes can be located by analogy with BA [ 8 ] , while the N--D in-plane bending modes appear at 1055 cm -~. The modes associated with the ethyl groups again give relatively weak absorptions and are difficult to assign with certainty. 8 0 0 - - 1 5 0 c m -1 r e g i o n
In this region, two NH(ND) out-of-plane bending modes, six C=O and six ring bending modes are e xpe c t e d plus two CH2 rocking modes, six CCC bending modes and two m e t h y l torsions associated with the ethyl groups. The N--H out-of-plane bending modes appear as a band at 669 cm -~, with
35 a low f r e q u e n c y shoulder in an argon matrix, shifting to ca. 850 cm -' in the dimer or in the solid phase. In a nitrogen matrix the m o n o m e r bands are shifted a b o u t 20 cm -~ to higher frequencies, but no additional band was observed (unlike BA or MBA). Weak but sharp bands appear in the solid spectrum between 800 and 780 cm -~ which must be combination bands enhanced in intensity by interaction with the nearby N--H out-of-plane bending modes. Mesley [3] n o t e d such bands as a characteristic of barbiturate spectra, but t h e y were n o t observed in t he spectra of solid BA or MBA. The skeletal vibrations of the ring are readily assigned by analogy with barbituric acid [ 8 ] . T he characteristic ring breathing m o d e gives an intense Raman band at 610 cm -~ for the m o n o m e r in an argon matrix and at 627 cm -~ for the solid, but is t o o weak to observe in the infrared spectra. The modes associated with the ethyl groups are again difficult to assign. T he bands observed and their assignments are summarised in Tables 1 and 2. R e g i o n b e l o w 1 5 0 c m -~
In the R a m a n spectrum o f solid barbital, a n u m b e r of low frequency bands were observed at 123 cm -~ (w), 102 cm -~ (m), 88 cm -~ (m), 67 cm -~ (s) and 44 cm -~ (m). Deuterated barbital gave additional strong bands at 79 cm -1 and 31 cm -~. The only fundamentals e xpe c t e d in this region are the C--C torsions o f the ethyl groups, thus most o f these bands must be due to lattice modes. Similar bands were observed f or MBA [ 7 ] . CONCLUSIONS Comparison o f the spectra o f barbital and barbituric acid shows that the vibrations o f the pyrimidine ring occur with similar frequencies and relative intensities in th e t w o- c om pounds . Thus the vibrational spectra of the barbiturates can be discussed in terms o f the assignment obtained for barbituric acid [8] (or 1-methyl barbituric acid [7] for N-methyl substituted barbiturates). In the infrared, the N--H stretching, C=O stretching, C--N stretching, N--H in-plane and N--H out-of-plane bending modes give strong and characteristic absorptions. It should be n o t e d t hat the two lower frequency C--N stretching modes shift appreciably on deuteration. The C=O out-of-plane bending m o d e at ca. 750 cm -1 is also intense in the infrared spectrum of the m o n o m e r , b u t becomes weaker in the spectrum of the solid. The N--H stretching and bending and the C=O stretching modes are all {particularly the N--H out-of-plane bending m ode ) sensitive to intermolecular interactions and thus particularly useful in studying complexes of the barbiturates. In the Raman, the 4,6-C=O symmetric stretching and ring breathing modes give intense and characteristic bands. It is interesting that several of the bands listed b y Mesley [ 3 ] , in the infrared spectrum, or by Willis et al. [ 4 ] , in the Raman spectrum, as characteristic o f barbiturates in fact originate in the substituents rather than in the pyrimidine ring.
36 TABLE 1 C o m p a r i s o n o f infrared s p e c t r a ( c m - ' ) o f barbital in a r g o n matrices and t h e solid phasea Assignment NH s t r e t c h NH s t r e t c h
A' A~
CH s t r e t c h e s
6A', 4A"
1433 + 1323 4,6-C=O sym. s t r e t c h 1014 + 749 4,6-C=O asym. s t r e t c h 2-C=O s t r e t c h CH~ scissors
A' A" A" A' 2A'
CH 3 asym. def.
2A', 2A"
CN s t r e t c h CN s t r e t c h
A'
CH 3 s y m . def.
2A'
CH~ wags
A ,r
2A'
CH~ twists
2A"
NH i.p. b e n d NH i.p. b e n d
A n
CN s t r e t c h CN s t r e t c h
A" A'
CH 3 r o c k s
2A', 2A"
M o n o m e r / A r (20 K)
D i m e r / A r (20 K )
Solid (20 K)
3430 (s)
3210 (br) 3110 (br) ----
3245 (s) 3082 (s) 2988 (w) 2977 (w) 2962 b 2943 ( w ) 2926 b 2884 (mw) 2864 (sh) 2742 b 1759 (s) 1741 (w)
-
-
-
-
2984 ( m w ) ~2962 b ~2951 (w) ] 2 9 2 4 (vw) | 2 8 9 0 (vw) ~ 2 8 6 0 (vw) _ 1776 (s) 1740 (w) 1757 (vs) 1726 (vs) 1506 (w) 1468 (vw) 1462 (w) 1449 (w) 1433 (vw) 1426 (s) 1405 (m) 1394 (vw) 1379
CC s t r e t c h e s
A ,I
A' 4A'
A' 2A"
n" A'
(m) (m) (s) (m) (w)
--
--1332 1319
1362 1353 1333 1323
(sh) (vw) (s) (s)
1374 1307 1234 1175
(s) (m) (s) (w)
-
1305 1301 1279 1225 1167
(sh) (s) (w) (m) (w)
1375 -1237 1175
1101
(vw)
--
1095 (vw) -
1040 (w) 1014 (w) 943 (vw) --
A ,t
(vs, br)
--
-
768 (w) C=O o.p. b e n d C=O o.p. b e n d CH 2 r o c k s NH o.p. b e n d NH o.p. b e n d
1705 --1464 1451 -1433 1412 1392
(vw)
-
CC s t r e t c h (ring) CC s t r e t c h (ring)
---_ --~1750 1714 -----1433 1420 --
1364 (w) 1341 (w) 1330 (w) -
A'
--
758 749 738 669 662
(w) (s) (w) (s) (sh)
-1056 -1023 -----739 --
870 (br)
--
1085 b 1059 (vw) 1045 (w) 1027 b 945 (vw) 937 (vw) 899 (w, br) 763, . 760 (vw) 747 737 712 864 831
(w) (w) (w) (m) (m)
37 TABLE 1 (continued) Assignment
M o n o m e r / A r (20 K)
A" A'
--
801
--
--
788 (w)
--
781
ring i.p. b e n d ring i.p. b e n d C=O i.p. b e n d C=O i.p. b e n d CCC b e n d s CH 3 t o r s i o n s ring o.p. b e n d ring o.p. b e n d ring o . p . b e n d CC t o r s i o n s
A" A' A' A.
654 (w) 610 b 607 (w) 500 (sh) 492 (m) 448 (w) -.
A'
4A
. ', 2A
"
2A . A' A.
.
--
. --
.
.
199 c 172 c 158 c
. --
.
(w)
. --
--
.
(w)
673 (w) 627 b 614 (w) 509 (w) 500 (s) 457 (w) 424 (w) 409 (m) 368 c
496 ---
-.
A'
2A .
645 ---
--
.
Solid (20 K )
--
--
C=O i.p. b e n d ring b r e a t h i n g C=O o.p. b e n d
D i m e r / A r (20 K )
.
.
aAbbreviations used: (vs) very s t r o n g ; (s) strong; (ms) m e d i u m s t r o n g ; (m) m e d i u m ; ( m w ) m e d i u m w e a k ; (w) w e a k ; (vw) very w e a k ; (br) b r o a d ; (sh) s h o u l d e r ; i.p. in-plane; o.p. outof-plane, b F r e q u e n c y t a k e n f r o m R a m a n s p e c t r u m (very w e a k in infrared). CRoom temperature. TABLE 2 C o m p a r i s o n o f infrared s p e c t r a ( c m - ' ) o f 1 , 3 - d i d e u t e r o - 5 , 5 - d i e t h y l barbituric acid in argon m a t r i c e s and t h e solid p h a s e Assignment
M o n o m e r / A r (20 K ) --
( 2 9 8 4 (m) --
CH s t r e t c h e s
6A', 4A"
2963 (vw) 2949 (w) 2924 (vw) 2889 ( w ) 2 8 6 0 (vw)
1428 + 1335 1428 + 1322
A"
ND s t r e t c h
A'
ND s t r e t c h
A"
--
A'
2531 (w) 1769 (s)
4,6-C=O sym. s t r e t c h
A'
__ __ 2560 (w) 2552 (sh) 2542 (m)
D i m e r / A r (20 K) --------
--
Solid (20 K) 2989 (vw) 2977 (w) 2969 (vw) 2962 a 2945 (w, br) 2923 a 2883 (vw) 2 8 5 5 (vw, b r )
__ __ --2405 (sh) 2358 (br) 2340 (sh)
2326 (m, br)
2 2 9 2 (br)
2 2 9 2 (m)
---
2753 a 2745 a --2405 (m)
-1756 (ms)
38 TABLE 2 (continued) Assignment
Monomer/Ar
(20 K)
Dimer/Ar (20 K)
Solid (20 K) 1744 a 1703 a 1 6 8 4 (vs) 1644 a -1472 (vw) 1464 1454 1446 1428 1414
1262 + 491 4,6-C=O asym. stretch 2-C=O stretch
A' A"
CH 2 scissors
2A'
1503 (vw) 1470 (sh)
-1707 1690 __ ---
CH 3 asym. def.
2 A ' , 2A"
CN stretch CN stretch
A" A'
1461 1456 1445 1408 1397
(w) (sh) (m) (s) (s)
---1437 1423
CH 3 sym. def.
2A'
{ 1 3 8 3 (s) 1377 (m)
---
1402 (m) 1391 (w)
CH 2 wags
2A'
{ 1349 (w) 1 3 3 5 (s)
---
1343 (w) 1335 (m)
CH 2 twists
2A"
CN stretch CN stretch
A" A'
{ 1318 (w) -1262 (m) 1219 (m)
--1276 --
1199 (w)
--
1148 (m)
--
1748 (m) 1 7 3 3 (vs) 1 7 2 3 (vs)
A'
__
647 + 506
A'
CH3 r o c k s
2A'
N D i.p. b e n d s
A',A"
{ 1100 (vw) 1094 (vw) 1055 (m)
CH3 r o c k s
2A"
l10
CC stretch (ring)
A"
CC s t r e t c h e s
4A'
CC stretch (ring) C=O o.p. bend C=O o.p. bend
A' A" A'
CH2 r o c k s
2A"
C=O
i.p. b e n d
I t
A"
breathing C=O o.p. bend ND o.p. bend ND o.p. bend
A'
r i n g i.p. b e n d r i n g i.p. b e n d C = O i.p. b e n d C = O i.p. b e n d
A" A' A' A.
ring
I !
A'
A' A"
.
40 (w) 937 (w) --
-854 758 745 730 726
(m) (w) (m) (w) (w)
653
(w)
647 (w) 635 (vw) 618 ( w ) 610 a 6 0 5 (vw) 5 0 6 (vs) --491 (m) 445 (m) -. .
1322 1308 1272 1234 1222 1206 1199 --
(w) (vw) (sh) (s) (s)
(w) (w) (m) (w, b r ) (w) (w, b r ) (w)
--1067
-1094 (vw) 1072 (m)
---891 875 864 766 755 ---
1051a 1042 (w) 941 (vw) 8 9 2 (vw) -856 (vw) 765 (m) 754 (m) 738 (w)
-
---
--610 (br) ------
--
648 (w) 637 a -
622 611 599 561 504 494 453 423 406
(row) (vw) (w) (row) (sh) (m) (w) (w) (w)
39 T A B L E 2 (continued) Assignment CCC bends CH 3 torsions ring o.p. bend ring o.p. bend ring o.p. bend CC torsions
M o n o m e r / A r (20 K) 4A', 2A . 2A . A' A. . A' 2A .
. .
.
. . -. -.
Solid (20 K) 361 b
. -. --
.
D i m e r / A r (20 K)
.
204 b 175 b 155 b
.
a F r e q u e n c y taken from R a m a n spectrum (very weak in infrared), b R o o m temperature. ACKNOWLEDGEMENTS
We are grateful to Professor W. J. Orville-Thomas for his encouragement of this work, and to Dr. M. A. Stuckey and P.J. Walkden for assistance in obtaining spectra. REFERENCES 1 W. C. Price, J. E. S. Bradley, R. D. B. Fraser and J. P. Quilliam, J. Pharm. Pharmacol., 6 (1954) 522. 2 S. G o e n e c h e a , Z. Anal. Chem., 218 (1966) 416. 3 R. J. Mesley. S p e c t r o c h i m . Acta, Fart A, 26 (1970) 1427. 4 J. N. Willis, Jr., R. B. C o o k and R. J a n k o w , Anal. Chem., 44 (1972) 1228. 5 A. Bult and H. B. Klasen, Spectrosc. Lett.. 9 (1976) 81. 6 Y. K y o g o k u , R. C. Lord and A. Rich, Nature (London), 218 (1968) 69. 7 A. J. Barnes, M. A. Stuckey, W. J. Orville-Thomas, L. Le Gall and J. Lauransan, J. Mol. Struct., 56 (1979) 1. 8 A. J. Barnes, L. Le Gall and J. Lauransan, J. Mol. Struct, 56 (1979) 15. 9 W. Bolton, Acta Crystallogr., 16 (1963) 166. 10 B. M. Craven, C. Cusatis, G. L. Gartland and E. A. Vizzini, J. Mol. Struct., 16 (1973) 331. 11 G. C. Percy and A. L. Rodgers, Spectrosc. Lett., 7 (1974) 431.
VIBRATIONAL SPECTRA OF BARBITURIC ACID DERIVATIVES IN LOW-TEMPERATURE MATRICES Part 3 . 5 , 5 - D i e t h v l b a r b i t u r i c acid ( b a r b i t a l )
A. J. BARNES
Department of Chemistry and Applied Chemistry, University of Salford, Salford M5 4WT (Gt. Britain)
L. LE GALL and J. LAURANSAN Laboratoire de Thermodynamique Chimique, Universit$ de Bretagne Occidentale, 6 Avenue le Gorgeu, 29283 Brest Cedex (France) (Received 28 March 1979)
ABSTRACT Infrared and Raman spectra are reported for 5,5-diethyl barbituric acid (barbital or barbitone), and for its deuterated counterpart, in argon and nitrogen matrices at different concentrations. Infrared, far infrared and Raman spectra of the solid phase were also obtained. The data enabled a vibrational assignment to be made for both the monomeric form and the solid. The modes which are characteristic of barbiturates are discussed. INTRODUCTION T h e i n f r a r e d s p e c t r u m o f b a r b i t a l has b e e n r e p o r t e d b y a n u m b e r o f a u t h o r s [ 1 - - 3 ] , a n d t h e R a m a n s p e c t r u m has also b e e n ob~mned [ 4 ] . As ~or o t h e r b a r b i t u r i c acid derivatives, detailed i n t e r p r e t a t i o n o f t h e s p e c t r a has largely b e e n c o n f i n e d t o t h e N - - H a n d C=O s t r e t c h i n g m o d e s , a n d t h e r e is c o n t r o versy o v e r the a s s i g n m e n t o f t h e b a n d s in t h e c a r b o n y l s t r e t c h i n g region. Mesley [3] has carried o u t a s t u d y o f p o l y m o r p h i s m in t h e b a r b i t u r a t e s , and details i n f r a r e d s p e c t r a o f f o u r distinct f o r m s o f solid barbital. I n f r a r e d spect r o s c o p y has b e e n used to s t u d y m e t a l c o m p l e x e s o f b a r b i t a l [5] and t h e h y d r o g e n - b o n d e d c o m p l e x o f b a r b i t a l w i t h a d e n i n e derivatives [ 6 ] . Matrix isolation v i b r a t i o n a l s p e c t r o s c o p y has e n a b l e d v i b r a t i o n a l assignm e n t s to be m a d e f o r b a r b i t u r i c acid a n d its 1 - m e t h y l a n d 1, 3 - d i m e t h y l subs t i t u t e d derivatives [7, 8 ] . I t is o f i n t e r e s t t o see w h e t h e r t h e a s s i g n m e n t can be e x t e n d e d to t h e p h a r m a c e u t i c a l l y i m p o r t a n t 5 , 5 - d i s u b s t i t u t e d derivatives such as barbital. An i n t e r p r e t a t i o n o f the v i b r a t i o n a l s p e c t r a o f b a r b i t u r a t e s w o u l d be o f o b v i o u s value in using i n f r a r e d o r R a m a n s p e c t r o s c o p y to s t u d y t h e b i n d i n g o f t h e drugs t o c o m p o u n d s such as a d e n i n e derivatives.
30 EXPERIMENTAL
The experimental details are similar to those described in Part 1 [7]. The barbital was obtained from Merck, and the deuterated c o m p o u n d was prepared by exchange with D20. RESULTS
Infrared spectra of barbital in argon matrices were recorded after deposition
0
from samples of the solid held at temperatures of 66°C, 77°C, 90°C and 100°C {the melting point of barbital is 190°C). Infrared spectra were also recorded of barbital in nitrogen matrices, and of barbital in argon matrices doped with 1% nitrogen. A spectrum of pure solid barbital was obtained by deposition at 20 K, annealing the solid at room temperature overnight, and then recooling to 20 K. Infrared spectra of the solid in a CsBr disc and far infrared spectra in a vaseline mull were also recorded. Spectra obtained in the N--H stretching region are compared in Fig. 1 (note that the quantity of barbital deposited differed from one sample to another). Deposition from the solid held at 66°C gave virtually only monomeric barbital, while deposition from the solid held at 100°C gave a mixture of m o n o m e r and dimer. A Raman spectrum of barbital in an argon matrix was recorded after deposition from a sample held at 75°C, and the Raman spectrum o f the pure solid was also recorded. The low temperature Raman spectrum of the solid showed evidence of polymorphism, splitting of m a n y bands being observed. Infrared spectra of 1,3-dideutero-5,5-diethyl barbituric acid (d-barbital) in argon matrices were recorded after deposition from samples of the solid held at temperatures in the range 66--105°C, and a spectrum of the pure solid was also obtained at 20 K. Raman spectra were recorded in an argon matrix, after deposition from a sample of the solid held at 75°C, and of the pure solid at 20 K. The spectra of barbital and d-barbital in the region 1500--400 cm -1 are compared in Fig. 2. DISCUSSION
According to the X-ray crystal structure determination [ 9], the ring in barbituric acid is significantly distorted from planarity, in such a way that the methylene part of the ring has a boat-shaped configuration. Assuming that the
31
3600
2600 ~, (crn-')
Fig. 1. Infrared spectra of the N--H stretching region of barbital (deposited from the solid held at different temperatures 0°C) in argon matrices and in the solid phase at 20 K.
isolated barbital molecule has a similar structure, it m a y retain the s y m m e t r y of barbituric acid, i.e. Cs. The 69 normal modes of vibration, of which 36 are associated with internal vibrations of the ethyl groups, then divide into 39 A' and 30 A" modes. Craven et al. [10] have reported crystal structures of three forms of solid barbital: barbital I has a structure identical to that of solid barbituric acid, i.e. the molecules are linked through the carbonyls in the 2 and 4 positions, barbital II has the molecules linked through the carbonyls in the 4 and 6 positions while barbital IV has the molecules linked by two hydrogen bonds to the carbonyl in the 4 position. In the dimer and in forms I and IV of the solid phase the plane of s y m m e t r y in the barbital m o n o m e r is lost. 4000--1800
c m -1 r e g i o n
Twelve modes are expected in this region: two NH(ND) stretching vibrations and ten CH stretching modes associated with the ethyl groups. Barbital gives only one band in the NH stretching region, whereas d-barbital has several weak bands close to the principal N--D stretching absorption. One of these may be
32
Ba rbi ta I
I
I
I
I
I
I
J
I
I
I
L
[
I
[
D-Barbital
V I I400
I 1200
I
I
I
1000
800
600
400
(cm -t )
Fig. 2. Infrared spectra of the 1500--400 cm -1 region of barbital and deuterated barbital (deposited from the solids held at 66°C) in argon matrices at 20 K.
t h e s e c o n d N - - D s t r e t c h i n g m o d e . T h e e f f e c t o f association o n t h e N - - H s t r e t c h i n g m o d e s is similar to t h a t f o u n d f o r b a r b i t u r i c acid. 1800--1600
c m -~ region
T h r e e c a r b o n y l s t r e t c h i n g m o d e s are e x p e c t e d in this region, w h o s e assignm e n t has b e e n t h e s u b j e c t o f c o n t r o v e r s y . In an a r g o n m a t r i x , t h e highest freq u e n c y b a n d ( 1 7 7 6 c m -~) is relatively w e a k in t h e infrared b u t intense in t h e R a m a n s p e c t r u m , while the l o w e r f r e q u e n c y b a n d s ( 1 7 5 7 a n d 1 7 2 6 c m -1) are intense in t h e i n f r a r e d b u t w e a k in t h e R a m a n s p e c t r u m (Fig. 3). This is
33
!
:-J (
[a)
_2_
I
i
]
!
1800 1700 1600 1800 1700 16001800 ~, ( cm -r)
I
t
(d)
L<
1700 1600 1800 1700 1600
Fig. 3. Carbonyl stretching region of barbital. A, IR spectrum in argon matrix; B, Raman spectrum in argon matrix; C, IR spectrum in solid phase (20 K); D, Raman spectrum in solid phase (room temperature).
analogous to the results for barbituric acid and its N-methyl substituted derivatives [7, 8]. Thus the highest frequency band is assigned to the 4,6-C=O symmetric stretch, the middle band to the 4,6-C=O antisymmetric stretch and the lowest frequency band to the 2-C=O stretch. Percy and Rodgers [11] arrived at the same assignment from infrared spectra of barbiturate complexes. The solid spectrum was complicated by polymorphism: two forms of the solid were found, each with two bands in the infrared or Raman spectrum of this region, at ca. 1760 and 1700 cm -1 or at ca. 1730 and 1690 cm -' (the latter is probably barbital I in view o f the similarity of the frequencies to those of BA). The higher frequency band in either form is the more intense in the Raman spectrum, and is clearly the 4,6-C=O symmetric stretch, while the lower frequency band is the more intense in the infrared spectrum and contains the other two carbonyl stretching modes. Other barbiturates apparently have the 4,6-C=O symmetric stretch near 1737 cm -1 [4]. 1600--1150
c m -1
region
In this region, barbital and d-barbital should show four ring C--N stretches plus twelve m e t h y l and methylene deformation modes associated with the ethyl groups. Additionally barbital should have two N--H in-plane bending modes. The C--N stretching modes are readily identified by comparison with BA (barbituric acid) and DBA [8], and the N--H in-plane bending modes appear in an argon matrix as a band at 1301 cm-' with a high frequency shoulder (Fig. 4). Unlike BA or MBA (1-methyl barbituric acid) there seems
34
©
r
8 : 66°C
L
I
I
[500
1400
1500
I
I
90%
E
12001500 1400
I 1500
L
IO0°C
I
t20015001400
I 1500
I
Pore
I
E
1 2 0 0 1 5 0 0 1400
I
I
1500
[200
v [cm -q )
Fig. 4. Infrared spectra of the 1500--1200 cm-1 region of barbital (deposited from the solid held at different temperatures 0°C) in argon matrices and in the solid phase at 20 K. to be no interaction with the overtones of the N--H out-of-plane bending modes, and only a small shift was observed between the argon and nitrogen matrix frequencies. The modes associated with the ethyl groups all give relatively weak absorptions and can only be assigned tentatively. 1 1 5 0 - - 8 0 0 c m -~ region
In this region two ring C--C stretches plus four m e t h y l rocking modes and fo ur C--C stretches associated with the ethyl groups are expected for both barbital and d-barbital. T he deuterated c o m p o u n d should show additionally the two N--D in-plane bending modes. The ring C--C stretching modes can be located by analogy with BA [ 8 ] , while the N--D in-plane bending modes appear at 1055 cm -~. The modes associated with the ethyl groups again give relatively weak absorptions and are difficult to assign with certainty. 8 0 0 - - 1 5 0 c m -1 r e g i o n
In this region, two NH(ND) out-of-plane bending modes, six C=O and six ring bending modes are e xpe c t e d plus two CH2 rocking modes, six CCC bending modes and two m e t h y l torsions associated with the ethyl groups. The N--H out-of-plane bending modes appear as a band at 669 cm -~, with
35 a low f r e q u e n c y shoulder in an argon matrix, shifting to ca. 850 cm -' in the dimer or in the solid phase. In a nitrogen matrix the m o n o m e r bands are shifted a b o u t 20 cm -~ to higher frequencies, but no additional band was observed (unlike BA or MBA). Weak but sharp bands appear in the solid spectrum between 800 and 780 cm -~ which must be combination bands enhanced in intensity by interaction with the nearby N--H out-of-plane bending modes. Mesley [3] n o t e d such bands as a characteristic of barbiturate spectra, but t h e y were n o t observed in t he spectra of solid BA or MBA. The skeletal vibrations of the ring are readily assigned by analogy with barbituric acid [ 8 ] . T he characteristic ring breathing m o d e gives an intense Raman band at 610 cm -~ for the m o n o m e r in an argon matrix and at 627 cm -~ for the solid, but is t o o weak to observe in the infrared spectra. The modes associated with the ethyl groups are again difficult to assign. T he bands observed and their assignments are summarised in Tables 1 and 2. R e g i o n b e l o w 1 5 0 c m -~
In the R a m a n spectrum o f solid barbital, a n u m b e r of low frequency bands were observed at 123 cm -~ (w), 102 cm -~ (m), 88 cm -~ (m), 67 cm -~ (s) and 44 cm -~ (m). Deuterated barbital gave additional strong bands at 79 cm -1 and 31 cm -~. The only fundamentals e xpe c t e d in this region are the C--C torsions o f the ethyl groups, thus most o f these bands must be due to lattice modes. Similar bands were observed f or MBA [ 7 ] . CONCLUSIONS Comparison o f the spectra o f barbital and barbituric acid shows that the vibrations o f the pyrimidine ring occur with similar frequencies and relative intensities in th e t w o- c om pounds . Thus the vibrational spectra of the barbiturates can be discussed in terms o f the assignment obtained for barbituric acid [8] (or 1-methyl barbituric acid [7] for N-methyl substituted barbiturates). In the infrared, the N--H stretching, C=O stretching, C--N stretching, N--H in-plane and N--H out-of-plane bending modes give strong and characteristic absorptions. It should be n o t e d t hat the two lower frequency C--N stretching modes shift appreciably on deuteration. The C=O out-of-plane bending m o d e at ca. 750 cm -1 is also intense in the infrared spectrum of the m o n o m e r , b u t becomes weaker in the spectrum of the solid. The N--H stretching and bending and the C=O stretching modes are all {particularly the N--H out-of-plane bending m ode ) sensitive to intermolecular interactions and thus particularly useful in studying complexes of the barbiturates. In the Raman, the 4,6-C=O symmetric stretching and ring breathing modes give intense and characteristic bands. It is interesting that several of the bands listed b y Mesley [ 3 ] , in the infrared spectrum, or by Willis et al. [ 4 ] , in the Raman spectrum, as characteristic o f barbiturates in fact originate in the substituents rather than in the pyrimidine ring.
36 TABLE 1 C o m p a r i s o n o f infrared s p e c t r a ( c m - ' ) o f barbital in a r g o n matrices and t h e solid phasea Assignment NH s t r e t c h NH s t r e t c h
A' A~
CH s t r e t c h e s
6A', 4A"
1433 + 1323 4,6-C=O sym. s t r e t c h 1014 + 749 4,6-C=O asym. s t r e t c h 2-C=O s t r e t c h CH~ scissors
A' A" A" A' 2A'
CH 3 asym. def.
2A', 2A"
CN s t r e t c h CN s t r e t c h
A'
CH 3 s y m . def.
2A'
CH~ wags
A ,r
2A'
CH~ twists
2A"
NH i.p. b e n d NH i.p. b e n d
A n
CN s t r e t c h CN s t r e t c h
A" A'
CH 3 r o c k s
2A', 2A"
M o n o m e r / A r (20 K)
D i m e r / A r (20 K )
Solid (20 K)
3430 (s)
3210 (br) 3110 (br) ----
3245 (s) 3082 (s) 2988 (w) 2977 (w) 2962 b 2943 ( w ) 2926 b 2884 (mw) 2864 (sh) 2742 b 1759 (s) 1741 (w)
-
-
-
-
2984 ( m w ) ~2962 b ~2951 (w) ] 2 9 2 4 (vw) | 2 8 9 0 (vw) ~ 2 8 6 0 (vw) _ 1776 (s) 1740 (w) 1757 (vs) 1726 (vs) 1506 (w) 1468 (vw) 1462 (w) 1449 (w) 1433 (vw) 1426 (s) 1405 (m) 1394 (vw) 1379
CC s t r e t c h e s
A ,I
A' 4A'
A' 2A"
n" A'
(m) (m) (s) (m) (w)
--
--1332 1319
1362 1353 1333 1323
(sh) (vw) (s) (s)
1374 1307 1234 1175
(s) (m) (s) (w)
-
1305 1301 1279 1225 1167
(sh) (s) (w) (m) (w)
1375 -1237 1175
1101
(vw)
--
1095 (vw) -
1040 (w) 1014 (w) 943 (vw) --
A ,t
(vs, br)
--
-
768 (w) C=O o.p. b e n d C=O o.p. b e n d CH 2 r o c k s NH o.p. b e n d NH o.p. b e n d
1705 --1464 1451 -1433 1412 1392
(vw)
-
CC s t r e t c h (ring) CC s t r e t c h (ring)
---_ --~1750 1714 -----1433 1420 --
1364 (w) 1341 (w) 1330 (w) -
A'
--
758 749 738 669 662
(w) (s) (w) (s) (sh)
-1056 -1023 -----739 --
870 (br)
--
1085 b 1059 (vw) 1045 (w) 1027 b 945 (vw) 937 (vw) 899 (w, br) 763, . 760 (vw) 747 737 712 864 831
(w) (w) (w) (m) (m)
37 TABLE 1 (continued) Assignment
M o n o m e r / A r (20 K)
A" A'
--
801
--
--
788 (w)
--
781
ring i.p. b e n d ring i.p. b e n d C=O i.p. b e n d C=O i.p. b e n d CCC b e n d s CH 3 t o r s i o n s ring o.p. b e n d ring o.p. b e n d ring o . p . b e n d CC t o r s i o n s
A" A' A' A.
654 (w) 610 b 607 (w) 500 (sh) 492 (m) 448 (w) -.
A'
4A
. ', 2A
"
2A . A' A.
.
--
. --
.
.
199 c 172 c 158 c
. --
.
(w)
. --
--
.
(w)
673 (w) 627 b 614 (w) 509 (w) 500 (s) 457 (w) 424 (w) 409 (m) 368 c
496 ---
-.
A'
2A .
645 ---
--
.
Solid (20 K )
--
--
C=O i.p. b e n d ring b r e a t h i n g C=O o.p. b e n d
D i m e r / A r (20 K )
.
.
aAbbreviations used: (vs) very s t r o n g ; (s) strong; (ms) m e d i u m s t r o n g ; (m) m e d i u m ; ( m w ) m e d i u m w e a k ; (w) w e a k ; (vw) very w e a k ; (br) b r o a d ; (sh) s h o u l d e r ; i.p. in-plane; o.p. outof-plane, b F r e q u e n c y t a k e n f r o m R a m a n s p e c t r u m (very w e a k in infrared). CRoom temperature. TABLE 2 C o m p a r i s o n o f infrared s p e c t r a ( c m - ' ) o f 1 , 3 - d i d e u t e r o - 5 , 5 - d i e t h y l barbituric acid in argon m a t r i c e s and t h e solid p h a s e Assignment
M o n o m e r / A r (20 K ) --
( 2 9 8 4 (m) --
CH s t r e t c h e s
6A', 4A"
2963 (vw) 2949 (w) 2924 (vw) 2889 ( w ) 2 8 6 0 (vw)
1428 + 1335 1428 + 1322
A"
ND s t r e t c h
A'
ND s t r e t c h
A"
--
A'
2531 (w) 1769 (s)
4,6-C=O sym. s t r e t c h
A'
__ __ 2560 (w) 2552 (sh) 2542 (m)
D i m e r / A r (20 K) --------
--
Solid (20 K) 2989 (vw) 2977 (w) 2969 (vw) 2962 a 2945 (w, br) 2923 a 2883 (vw) 2 8 5 5 (vw, b r )
__ __ --2405 (sh) 2358 (br) 2340 (sh)
2326 (m, br)
2 2 9 2 (br)
2 2 9 2 (m)
---
2753 a 2745 a --2405 (m)
-1756 (ms)
38 TABLE 2 (continued) Assignment
Monomer/Ar
(20 K)
Dimer/Ar (20 K)
Solid (20 K) 1744 a 1703 a 1 6 8 4 (vs) 1644 a -1472 (vw) 1464 1454 1446 1428 1414
1262 + 491 4,6-C=O asym. stretch 2-C=O stretch
A' A"
CH 2 scissors
2A'
1503 (vw) 1470 (sh)
-1707 1690 __ ---
CH 3 asym. def.
2 A ' , 2A"
CN stretch CN stretch
A" A'
1461 1456 1445 1408 1397
(w) (sh) (m) (s) (s)
---1437 1423
CH 3 sym. def.
2A'
{ 1 3 8 3 (s) 1377 (m)
---
1402 (m) 1391 (w)
CH 2 wags
2A'
{ 1349 (w) 1 3 3 5 (s)
---
1343 (w) 1335 (m)
CH 2 twists
2A"
CN stretch CN stretch
A" A'
{ 1318 (w) -1262 (m) 1219 (m)
--1276 --
1199 (w)
--
1148 (m)
--
1748 (m) 1 7 3 3 (vs) 1 7 2 3 (vs)
A'
__
647 + 506
A'
CH3 r o c k s
2A'
N D i.p. b e n d s
A',A"
{ 1100 (vw) 1094 (vw) 1055 (m)
CH3 r o c k s
2A"
l10
CC stretch (ring)
A"
CC s t r e t c h e s
4A'
CC stretch (ring) C=O o.p. bend C=O o.p. bend
A' A" A'
CH2 r o c k s
2A"
C=O
i.p. b e n d
I t
A"
breathing C=O o.p. bend ND o.p. bend ND o.p. bend
A'
r i n g i.p. b e n d r i n g i.p. b e n d C = O i.p. b e n d C = O i.p. b e n d
A" A' A' A.
ring
I !
A'
A' A"
.
40 (w) 937 (w) --
-854 758 745 730 726
(m) (w) (m) (w) (w)
653
(w)
647 (w) 635 (vw) 618 ( w ) 610 a 6 0 5 (vw) 5 0 6 (vs) --491 (m) 445 (m) -. .
1322 1308 1272 1234 1222 1206 1199 --
(w) (vw) (sh) (s) (s)
(w) (w) (m) (w, b r ) (w) (w, b r ) (w)
--1067
-1094 (vw) 1072 (m)
---891 875 864 766 755 ---
1051a 1042 (w) 941 (vw) 8 9 2 (vw) -856 (vw) 765 (m) 754 (m) 738 (w)
-
---
--610 (br) ------
--
648 (w) 637 a -
622 611 599 561 504 494 453 423 406
(row) (vw) (w) (row) (sh) (m) (w) (w) (w)
39 T A B L E 2 (continued) Assignment CCC bends CH 3 torsions ring o.p. bend ring o.p. bend ring o.p. bend CC torsions
M o n o m e r / A r (20 K) 4A', 2A . 2A . A' A. . A' 2A .
. .
.
. . -. -.
Solid (20 K) 361 b
. -. --
.
D i m e r / A r (20 K)
.
204 b 175 b 155 b
.
a F r e q u e n c y taken from R a m a n spectrum (very weak in infrared), b R o o m temperature. ACKNOWLEDGEMENTS
We are grateful to Professor W. J. Orville-Thomas for his encouragement of this work, and to Dr. M. A. Stuckey and P.J. Walkden for assistance in obtaining spectra. REFERENCES 1 W. C. Price, J. E. S. Bradley, R. D. B. Fraser and J. P. Quilliam, J. Pharm. Pharmacol., 6 (1954) 522. 2 S. G o e n e c h e a , Z. Anal. Chem., 218 (1966) 416. 3 R. J. Mesley. S p e c t r o c h i m . Acta, Fart A, 26 (1970) 1427. 4 J. N. Willis, Jr., R. B. C o o k and R. J a n k o w , Anal. Chem., 44 (1972) 1228. 5 A. Bult and H. B. Klasen, Spectrosc. Lett.. 9 (1976) 81. 6 Y. K y o g o k u , R. C. Lord and A. Rich, Nature (London), 218 (1968) 69. 7 A. J. Barnes, M. A. Stuckey, W. J. Orville-Thomas, L. Le Gall and J. Lauransan, J. Mol. Struct., 56 (1979) 1. 8 A. J. Barnes, L. Le Gall and J. Lauransan, J. Mol. Struct, 56 (1979) 15. 9 W. Bolton, Acta Crystallogr., 16 (1963) 166. 10 B. M. Craven, C. Cusatis, G. L. Gartland and E. A. Vizzini, J. Mol. Struct., 16 (1973) 331. 11 G. C. Percy and A. L. Rodgers, Spectrosc. Lett., 7 (1974) 431.