- Email: [email protected]
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
CHAPTER 6
N-HETEROAROMATIC COMPOUNDS (POLYAZINES) THE principal effect of the introduction of further nitrogen atoms into the Nheteroaromatic ring is to shift the n -> π* band to longer wavelengths. Such displacements are dependent on the position rather than the number of azasubstituents. For example, .sym-triazine (I) shows the smallest and 3,5,6-trimethyl-l,2,4-triazine (II) the second largest bathochromic shift of the n -► π* band. The n -► π* bands of the polyazines are moved to lower wave-lengths on changing from hydrocarbon to hydroxylic solvent. In the latter solvent-type the hydrogen bonding of the /7-electrons of nitrogen results in a greater energy requirement for the n -> π* transition than that obtaining in the promotion of the electron in hydrocarbon solvent. Molecular orbital calculations show that in the 1,2-diazines (as III) ground state interaction between the nitrogen /?orbitals becomes an important factor, and the n -> π* bands are displaced by 6000 cm"1 from the position of the pyridine n -> π* band. In 1,3- and 1,4diazines such ground-state interaction is less, but the observed shift (relative to pyridine) is 3000 cm"1. This shift has been ascribed by Mason to a lowering of energy of the unoccupied π-orbitals on aza-substitution. M.O. calculations gave agreement to within 1000 cm"1 of observed shifts. The spectra of the polyazines in acidic solution show no n -» π* absorption. 1
n
N N V I
1
N
1 N
II
III
N V
Λ
N
IV
» VI
The first π -> π* band (i.e., long wavelength π -> π* band) of the polyazines may be compared with the 255 τημ benzene band. The intensity increments for polyaza-substitution when calculated by use of equation (2) (p. 187) give fair agreement with observed values. This method of correlation should be re garded as a useful qualitative working rule, however, which indicates a trend IUS7a
191
192
THE ULTRAVIOLET SPECTRA OF NATURAL
PRODUCTS
rather than an accurate means of predicting intensity data. Thus, the first 71 —> 71 band intensities of pyridazine (III) and pyrimidine (IV) should be equal, and those of pyrazine (V) and s-tetrazine (VI) should also be equal, but the 1,2diaza member of each pair absorbs with the lower intensity. Some generalizations are possible within each series as a result of empirical correlations made by investigators seeking confirmation of structural proposals (5). For example, it is found that a pyrimidine has the intensity of the first 71 —> 71 band reduced and only slightly shifted towards the red by a carboxyl group at the 2- and 5-positions, whereas the 4-C02H group gives a large red shift and intensity increase. 2- and 5-OH or OMe substitution, on the other hand gives rise to increased intensity and a bathochromic shift, the change for 4substitution by these functions being almost zero. Thesefindingsare in harmony with perturbation theory and qualitatively agree with the intensities derivable from the spectroscopic moments of the substituents (see p. 181). 6.1. P Y R I M I D I N E S
Pyrimidine (IV) has maxima at 243 τημ (π -► π*) and 298 ναμ (η -> π*) in cyclohexane solution. In hydroxylic solvents the 243 τημ band shows an inten sity increase (ε 3000 -► 5000) without positional changes, while the n -► π* band now appears at 271 m//. The blue shift of 27τημ for the change from nonpolar to polar solvent forms a measure of the electron donating capacity of the azine system. In polar media the /^-electrons of nitrogen form hydrogen bonds with the solvent so that the n -> π* transition requires more energy to weaken or break the H-bonds. The n -» π* band of pyrimidine disappears on cation formation. These phenomena are summarized in the data of Table 6.1. Hydroxypyrimidines may exist as the enol (VII) zwitterion or amide (VIII), cationic (IX) or anionic (X) forms, depending on structural environment (e.g. position of substituent) and on the pH and nature of the solvent. The favoured
H°-"N'
O/UHJ
H<^N"
VII
VIII
IX
^ f N
^N\OH XI
H 0
\
eo/W X
.Λ Y N
W
XII
side of an equilibrium state of a hydroxy-azine is usually measured by compar ison of the spectrum of the tautomerie mixture with that of the corresponding N- and O-methyl derivatives at the appropriate pH (p. 181). However, the
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
193
TABLE 6.1. PRINCIPAL ABSORPTION BANDS OF THE PYRIMIDINES
Compound
Bandi
Bandii
Solvent
Reference
C
O)
243 (2030) 243 (3210) 242 (5500)
4NH2S04
(1) (1)
223 (7320)
260 (3740)
ρΗ6·2
(2)
227(11,100)
263 (3280)
pH 13
(2)
224 (9840)
251 (2920)
5 N H2S04
(2)
229 (10,200)
240 (14,600) 250 sh (2650)
221 (6800) 226 (9080)
269 (3900) 258 (2940)
227 (7700)
247 (3350) 238 sh (6800)
298t (300) 2711 (420)
w
OH
A
U
N
O©
x1 N n / OH
AN
1
w H O
II
pH 6 pHO
(2) (1)
1
Me O \\ (
N—Me
pH 5 2-5 N HCl
(2) (2)
pH 6-95 pHO
(2)
A
(3)
OMe
A. O
A ί ΝΗ H t Λ->π* band.
— υ
260 (6300)
194
THE ULTRAVIOLET SPECTRA OF NATURAL PRODUCTS TABLE 6.1—(contd.)
Compound
Solvent
Bandi
Band II
—
268(10,000)
pH7
(3)
253 (8000) 263 (7500)
ρΗ7·6 pH 13
(3)
W
(3)
Reference
O
II ί|
Ν—Me
Me 0
{
l[
NH
XNiJ
222 (7000)
\)Me
O
II — k
H 0 /
g \
256-5 (25,000)
0
224 (13,000) 221 (14,800)
292 (3000) 302 (4000)
pH 7 pHl
(4)
233 (18,000) 236 (18,500)
268 (5000)
pH 13 pHO
(4)
250 (16,600) 262 (16,200)
286 (3600)
pH 9-3 pH 3-15
(4)
NH 2 1
II
NMe 2
II
interpretation of the electronic spectra of the hydroxydiazines is complicated by the contributions from two zwitterionic and two cationic forms. Both 2and 5-hydroxypyrimidines (XI and XII, respectively) have unique zwitterions OH
NH
N II
XIII
N
OM
oII
O
y/
XIV
'■\
II
11 IIN
H XV
XVI
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
195
by virtue of their symmetry. 4-Hydroxypyrimidine (XIII) has two amide forms (XIV) and (XV). The difference between the absorption curves of 4-hydroxypyrimidine and its O-methyl derivative (XVI) indicates that the compound (XIII) exists as a lactam. Comparison of the spectra of the isomerie N-Me derivatives (corresponding to XIV and XV) suggests that the y-form (XV) is preferred. Aminopyrimidines We recall that although 2- and 4-hydroxypyridines prefer to adopt the pyridone structure in solution, the aminopyridines are probably true amines and not imino-pyridones. This phenomenon is also observed in pyrimidine, whose amino derivatives may be considered as having —NH2 rather than imino functions. Basicity and infrared measurements also support such an assignment. OH
O
T
\
Ν
p N "
N
^ ζ ΝΗ
\)H
^
XVII
O
XVIIa Uracil
OH
O
λ
f N H0/W\0H XVIII
^
λ
(\ NH Η θ / γ \ > XVIII a Barbituric Acid
O ^
NH
XIX Alloxan
Biologically important oxygenated pyrimidines include uracil (XVII), bar bituric acid (XVIII), and alloxan (XIX). The spectroscopic data for these com pounds (Table 6.1) indicate substantial contributions from forms (XVIIa) and (XVIIIa). 6.2. PYRAZINES (TABLE 6.2)
Pyrazine (XX) absorbs at 260m// (e, 6000) and at 327m// (ε 100) in cyclohexane solution, the first band representing benzenoid absorption intensified by two aza-substituents (π -> π*) band and the weak band marking the n -► π*
196
THE ULTRAVIOLET SPECTRA OF NATURAL PRODUCTS TABLE 6.2. PYRAZINES
Compound
u /,Nv
θθΗ JTYY /γγ\> o Η
Bandi
Bandii
Solvent
Reference
327t (100)
260 (6300)
C
(5)
221 (8800) 222 (10,400)
317 (5520) 342 (6200)
pH5 10 N HaS04
(2)
234 (6500)
328 (8300)
A
(6)
480 (20,000)
Ch
(7)
500 (12,000)
Ch
(7)
550 (11,000)
Ch
(7)
363 (40,000)
A
(8)
Aspergillic acid O
t
(YY*) VwV
—
i
o
9 °H
cYn V^N^ t 1
; O
V
O OH
000 T i
—
OHO
CONH2 1
0CÓ t #ι->π* band.
250(120,000)
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
197
transition. Hydroxyl substitution produces the expected wavelength shift, e.g. 2-hydroxypyrazine (XXI) has λΏΙ&χ 317 τημ (ε 5500). 2-Hydroxypyrazine Noxide forms the chromophore of the mould metabolite aspergillic acid (XXII) Nv
/,N.
XX
XXI
o
o
XXII
XXIII
which has Amax 234 and 328 τημ (ε, 6500 and 8300) [cf. 2-hydroxypyridine Noxide (XXIII), ^max 228 and 305 m//]. Dibenzopyrazine-N-oxides occur as elaboration products of certain micro-organisms7. Some representatives of this class are illustrated in Table 6.2. 6.3. PURINES (TABLE 6.3)
Much of the early work devoted to the measurement of the ultraviolet spectra of hydroxyazines and especially the purines, is rendered inaccurate since in adequate control of solvent pH was maintained. As a result, the exact nature of the ionic species under study was often unknown. This situation has now been clarified by the work of Mason9, who has measured a large number of purine spectra using buffered solutions with pH values two units above (or below) the pK of the purine. The λια&χ and intensity values, at appropriate pH, of a selection of purines will be found in Table 6-3.
?Y>
H XXIV
H2N/^\NH? XXVI
XXV
je 2"*
H XXVII
The spectrum of purine (XXIV) (in aqueous solution) is reminiscent of that of pyrimidine. Greater similarity is evident when we compare the spectrum of 2-hydroxypurine with that of 2-hydroxy-4,5-diaminopyrimidine or 2-aminopurine (XXV) and 2,4,5-triaminopurine (XXVI). 2-Hydroxy and 2-amino substituents shift the main band at 260 τημ in both purines and 2,4,5-triaminopyrim-
198
THE ULTRAVIOLET SPECTRA OF NATURAL PRODUCTS TABLE 6.3. ABSORPTION SPECTRA OF PURINES9
Bandi
Compound
^
N
A
N H
3
/
9
ffy
Band II
< 220 (13,000) 260 (6200) < 220 (3000) 263 (7950) 219 (8300) 271 (7600)
264 (4700) 238 (2900) 271 (4800)
322 (6500) 315 (4900) 313 (4800)
pH
0-28 5-7 11
+
-0-75 6-05 10-15
+
-0-75 5-18 10-35
+
OH I 248 (10,500) 249 (10,500) 258(11,000)
H
MeO^
îj/
0
0
0
235 (3240)
280 (10,500) 277(11,000) 285 (12,900)
0 5-4 10-13
+
246 (2600)
284 (6760) 283 (8100) 283 (7600)
0 6 11-4
+
0-20 5-60 11-3
+
H
N/X
Charge of speciest
0
0
OMe 254 (10,000) 252 (9800) 261 (9800)
—
0
H 235 sh 237 sh 236 sh 276 sh
(6500) (4200) (5000) (4100)
325 314 305 303
(4200) (4000) (6020) (5750)
-3-5 1-84 7-0 12-0
++ +
2-1 7 12
+
0
NH 2 1
^ΝΛΝκ H
Adenine
262 (13,200) 260 (13,500) 267 (12,000)
—
0
N-HETERAROMATIC COMPOUNDS (POLYAZINES)
199
TABLE 6.3—(contd.) Compound
NMe 2 |
H
Bandi
Band II
pH
Charge of speciest
+
228 (33,000) 340 (3000) 223 (26,000) 332 (5000) 248 (10,500) 232 (25,000) 327 (4700)
12-7
276 (15,000) 275 (17,800) 221 (16,200) 281 (17,800)
1-7 6-98 13-0
+
1-7 6-98
0
0
OH
HO
/^NAN/
267 (7900) 277 (8300) 283 (8700)
5-05 9-99 13-0
0
240 (8000)
248 (10,700) 246 (10,200) 245 (6000) 221 (13,000)
271 (7100) 275 (7700) 273 (7400) 274 (8700)
1-0 6-2 10-71 13-0
+
OH
H 2 N/
H
0
t 0 Neutral molecule. + + Dication. + Cation. = Dianion. — Anion. idines to over 300 ταμ with a decrease in intensity from the parent value, whilst 6-hydroxy and -amino groups confer a blue shift and intensity increase relative to purine itself. The spectra of purines have two broad bands at 260 and below 220 m//. The 260 τημ band is shifted to longer wavelengths, for a given substituent, in the order 2 > 8 > 6-substituted purine (Table 6.3a). At the same time, the in tensity order for a given substituent is 8 > 6 > 2. Consideration of the avail able data has led to the view that the 260 τημ absorption is a composite band containing contributions from two transitions involving alternative polariz ations within the purine molecule (see XXVII). These polarizations are, re spectively, parallel and transverse to the major longitudinal axis. 8-Substituents exert an effect parallel to the main axis and therefore lower the energy of the stronger component of the 260 πιμ band. 6-Substituents are transversely dis-
200
T H E U L T R A V I O L E T S P E C T R A OF N A T U R A L TABLE 6.3a.
PRODUCTS
SUBSTITUT-TONAL INCREMENTS FOR THE P U R I N E N U C L E U S 9
]Position
Substituent
2
Species
in nucleus
6
8
shift of 260 m/i band (τημ) —NH 2
+
54 42 32
2 -3 -4
28 20 19
—NHMe
+
— — —
7 3 2
36 27 27
+
80 69 56
16 12 10
45 33 35
+
62 52 42
-12 -14 -13
20 14 14
+
24 20 14
-6 -10 -10
— — —
+
— — —
5 -2 0
4 3 3
0 — 0 —
—NMe a
0 —
—OH
0 —
—OMe
0 —
—Me
0 —
posed to this axis and affect the weaker component. Substituents at position-2 are disposed at an angle of 30° to the major axis and appear to affect both band components in shifting the entire band to the red. 2-Substituted purines ex hibit the following order of magnitude in shifting the 260 ιημ band: MeO < MeS < NH2 < HO < NMe2 < HS. The 6-and 8-derivatives show rather variable effects. Tautomerism to pyrimidone forms is marked in the hydroxypurines. For N RO/
-N v
> H
XXVIII
»Yv
HIN/A-NAN/
XXIX
XXX
example, the dissimilarity of the spectra of 2-hydroxy- and 2-methoxypurines (XXVIII; R = H and Me, respectively) and the similarity of the spectra of the amino purine (XXIX) and of its dimethyl derivative (XXX) form sugges tive (but not conclusive) evidence that the hydroxy purines may exist in the lactam form; while the amino compounds again may be considered as true —NH2 compounds.
N-HETEROAROMATIC COMPOUNDS (POLYANZINES)
201
The amino- and hydroxy-purines occur naturally as the bases of the nucleotides. Discussion of structural correlation and diagnosis employing the spectral data of these systems is referred to in Chapter 7 (p. 207).
6.4. PTERIDINES (TABLE 6.4)
Pteridine (XXXI) absorbs at 210,240,300 and 384 ma. The last band (e 80) H
o II
VN
fNìfNH
NAN^
XXXIII
XXXII
XXXI
marks the n -> π* transition and the remaining absorption is naphthalenoid with intensification caused by aza-nitrogen. Thus the 300 ιημ band (ε 7000) is to be compared with the corresponding naphthalene band at 310 τημ (ε 140). The calculated intensity (p. 187) for the 300 τημ band of pteridine is 10,000. The monohydroxypteridines are conveniently divided into two distinct spectral types. The 4- and 7-hydroxypteridines show three bands in neutral TABLE 6.4. PTERTOINES
Compound
8
Solvent
Reference
C
(5)
pH 7 pH13
(10)
375 (6000)
pH7 pH13
(10)
375 (2300)
309 (7800) 271 (4600) 313 (6400)
350 (3000)
pH7 pH13
(10)
230 (9600) 265 (3400) 242 (17,000) 257 (2700)
310 (6200) 333 (6000) 303 (9000)
ρΗ5·6 pH 10 pH 2-5
(10)
Bandi
Bandii
—
300 (7080)
230 (7600) 260 (7000)
307 (6800)
240 (8200) 236 (7800)
311 (7100) 312 (6500)
230 (9400) 236 (6800)
Band III 384 (80)
1
ι Ν ιΓ Ν Me
f^VWe OH
202
THE ULTRAVIOLET SPECTRA OF NATURAL PRODUCTS
solution and their curves are reminiscent of those of hydroxynaphthalenes. 4-Hydroxypteridine is mainly in the pteridone form (XXXII) although there is some evidence from infrared data that hydrogen bonding stabilizes the enol form (XXXIII) to a certain extent. This also is borne out by some similarities in the ultraviolet absorption of (XXXIII) and 4-methoxypteridine (XXXIV). The complexity of such data, however, indicates that we have reached the OMe
0
>NAN^ Me
XXXIV
XXXV
XXXVI
limit of usefulness of the comparison of the spectra of N-Me and O-Me deriv atives for purposes of assessing equilibria. The spectrum of 7-hydroxypteridine (XXXV) is, however, so similar to that of the pteridone (XXXVI) that the keto form is almost certainly preferred. It must be mentioned that the infrared specI tra of all hydroxypteridines show strong — C = 0 bands at 1670-90 cm * in the solid state. OH
- ίΝιΛ«
H
Yìf»
H XXXVII
XXXVIII
XXXIX
The 2-hydroxypteridines represent another category of pteridine spectra. Their absorption curves are complicated by reversible hydrate formation (XXXVII ^ XXXVIII). This is also true for 6-hydroxypteridine (XXXIX) which absorbs in the infrared at 1690 cm"1 and, Hke the 2-isomer, gives a two banded spectrum. Riboflavin (XL) contains the quinomethine chromophore of the pteridine nucleus within a tricyclic framework. The long wavelength band of riboflavin responsible for its colour occurs11 at 445 τημ (pH l). CH^CHOH^CHisOH
o XL
Riboflavin A 445 τημ
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
203
REFERENCES 1. S.F.MASON, / . Chem. Soc, 1247 (1959). 2. S.F.MASON, ibid., 1253 (1959). 3. J.R.MARSHALL and J.WALKER, ibid., 1004 (1951).
4. D.J.BROWN and L.N.SHORT, ibid., 331 (1953). 5. S.F.MASON, Chem. Soc. Special Publications, 3, 139 (1955). 6. G . D U N N , J.J.GALLAGHER, G.T.NEWBOLD and F.S.SPRING, / . Chem. Soc, 5126 (1949).
7. G.R.CLEMO and H.MCILWAIN, ibid., 479 (1938).
8. L.BIRHOFER, Ber. dtsch. ehem. Ges., 85, 1023 (1952). 9. S.F.MASON, / . Chem. Soc, 2071 (1954). 10. D.J.BROWN and S.F.MASON, ibid., 3443 (1956). 11. R.M.CRESSWELL, A . C . H I L L and H . C . S . W O O D , ibid., 698 (1959).
N-HETEROAROMATIC COMPOUNDS (POLYAZINES) THE principal effect of the introduction of further nitrogen atoms into the Nheteroaromatic ring is to shift the n -> π* band to longer wavelengths. Such displacements are dependent on the position rather than the number of azasubstituents. For example, .sym-triazine (I) shows the smallest and 3,5,6-trimethyl-l,2,4-triazine (II) the second largest bathochromic shift of the n -► π* band. The n -► π* bands of the polyazines are moved to lower wave-lengths on changing from hydrocarbon to hydroxylic solvent. In the latter solvent-type the hydrogen bonding of the /7-electrons of nitrogen results in a greater energy requirement for the n -> π* transition than that obtaining in the promotion of the electron in hydrocarbon solvent. Molecular orbital calculations show that in the 1,2-diazines (as III) ground state interaction between the nitrogen /?orbitals becomes an important factor, and the n -> π* bands are displaced by 6000 cm"1 from the position of the pyridine n -> π* band. In 1,3- and 1,4diazines such ground-state interaction is less, but the observed shift (relative to pyridine) is 3000 cm"1. This shift has been ascribed by Mason to a lowering of energy of the unoccupied π-orbitals on aza-substitution. M.O. calculations gave agreement to within 1000 cm"1 of observed shifts. The spectra of the polyazines in acidic solution show no n -» π* absorption. 1
n
N N V I
1
N
1 N
II
III
N V
Λ
N
IV
» VI
The first π -> π* band (i.e., long wavelength π -> π* band) of the polyazines may be compared with the 255 τημ benzene band. The intensity increments for polyaza-substitution when calculated by use of equation (2) (p. 187) give fair agreement with observed values. This method of correlation should be re garded as a useful qualitative working rule, however, which indicates a trend IUS7a
191
192
THE ULTRAVIOLET SPECTRA OF NATURAL
PRODUCTS
rather than an accurate means of predicting intensity data. Thus, the first 71 —> 71 band intensities of pyridazine (III) and pyrimidine (IV) should be equal, and those of pyrazine (V) and s-tetrazine (VI) should also be equal, but the 1,2diaza member of each pair absorbs with the lower intensity. Some generalizations are possible within each series as a result of empirical correlations made by investigators seeking confirmation of structural proposals (5). For example, it is found that a pyrimidine has the intensity of the first 71 —> 71 band reduced and only slightly shifted towards the red by a carboxyl group at the 2- and 5-positions, whereas the 4-C02H group gives a large red shift and intensity increase. 2- and 5-OH or OMe substitution, on the other hand gives rise to increased intensity and a bathochromic shift, the change for 4substitution by these functions being almost zero. Thesefindingsare in harmony with perturbation theory and qualitatively agree with the intensities derivable from the spectroscopic moments of the substituents (see p. 181). 6.1. P Y R I M I D I N E S
Pyrimidine (IV) has maxima at 243 τημ (π -► π*) and 298 ναμ (η -> π*) in cyclohexane solution. In hydroxylic solvents the 243 τημ band shows an inten sity increase (ε 3000 -► 5000) without positional changes, while the n -► π* band now appears at 271 m//. The blue shift of 27τημ for the change from nonpolar to polar solvent forms a measure of the electron donating capacity of the azine system. In polar media the /^-electrons of nitrogen form hydrogen bonds with the solvent so that the n -> π* transition requires more energy to weaken or break the H-bonds. The n -» π* band of pyrimidine disappears on cation formation. These phenomena are summarized in the data of Table 6.1. Hydroxypyrimidines may exist as the enol (VII) zwitterion or amide (VIII), cationic (IX) or anionic (X) forms, depending on structural environment (e.g. position of substituent) and on the pH and nature of the solvent. The favoured
H°-"N'
O/UHJ
H<^N"
VII
VIII
IX
^ f N
^N\OH XI
H 0
\
eo/W X
.Λ Y N
W
XII
side of an equilibrium state of a hydroxy-azine is usually measured by compar ison of the spectrum of the tautomerie mixture with that of the corresponding N- and O-methyl derivatives at the appropriate pH (p. 181). However, the
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
193
TABLE 6.1. PRINCIPAL ABSORPTION BANDS OF THE PYRIMIDINES
Compound
Bandi
Bandii
Solvent
Reference
C
O)
243 (2030) 243 (3210) 242 (5500)
4NH2S04
(1) (1)
223 (7320)
260 (3740)
ρΗ6·2
(2)
227(11,100)
263 (3280)
pH 13
(2)
224 (9840)
251 (2920)
5 N H2S04
(2)
229 (10,200)
240 (14,600) 250 sh (2650)
221 (6800) 226 (9080)
269 (3900) 258 (2940)
227 (7700)
247 (3350) 238 sh (6800)
298t (300) 2711 (420)
w
OH
A
U
N
O©
x1 N n / OH
AN
1
w H O
II
pH 6 pHO
(2) (1)
1
Me O \\ (
N—Me
pH 5 2-5 N HCl
(2) (2)
pH 6-95 pHO
(2)
A
(3)
OMe
A. O
A ί ΝΗ H t Λ->π* band.
— υ
260 (6300)
194
THE ULTRAVIOLET SPECTRA OF NATURAL PRODUCTS TABLE 6.1—(contd.)
Compound
Solvent
Bandi
Band II
—
268(10,000)
pH7
(3)
253 (8000) 263 (7500)
ρΗ7·6 pH 13
(3)
W
(3)
Reference
O
II ί|
Ν—Me
Me 0
{
l[
NH
XNiJ
222 (7000)
\)Me
O
II — k
H 0 /
g \
256-5 (25,000)
0
224 (13,000) 221 (14,800)
292 (3000) 302 (4000)
pH 7 pHl
(4)
233 (18,000) 236 (18,500)
268 (5000)
pH 13 pHO
(4)
250 (16,600) 262 (16,200)
286 (3600)
pH 9-3 pH 3-15
(4)
NH 2 1
II
NMe 2
II
interpretation of the electronic spectra of the hydroxydiazines is complicated by the contributions from two zwitterionic and two cationic forms. Both 2and 5-hydroxypyrimidines (XI and XII, respectively) have unique zwitterions OH
NH
N II
XIII
N
OM
oII
O
y/
XIV
'■\
II
11 IIN
H XV
XVI
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
195
by virtue of their symmetry. 4-Hydroxypyrimidine (XIII) has two amide forms (XIV) and (XV). The difference between the absorption curves of 4-hydroxypyrimidine and its O-methyl derivative (XVI) indicates that the compound (XIII) exists as a lactam. Comparison of the spectra of the isomerie N-Me derivatives (corresponding to XIV and XV) suggests that the y-form (XV) is preferred. Aminopyrimidines We recall that although 2- and 4-hydroxypyridines prefer to adopt the pyridone structure in solution, the aminopyridines are probably true amines and not imino-pyridones. This phenomenon is also observed in pyrimidine, whose amino derivatives may be considered as having —NH2 rather than imino functions. Basicity and infrared measurements also support such an assignment. OH
O
T
\
Ν
p N "
N
^ ζ ΝΗ
\)H
^
XVII
O
XVIIa Uracil
OH
O
λ
f N H0/W\0H XVIII
^
λ
(\ NH Η θ / γ \ > XVIII a Barbituric Acid
O ^
NH
XIX Alloxan
Biologically important oxygenated pyrimidines include uracil (XVII), bar bituric acid (XVIII), and alloxan (XIX). The spectroscopic data for these com pounds (Table 6.1) indicate substantial contributions from forms (XVIIa) and (XVIIIa). 6.2. PYRAZINES (TABLE 6.2)
Pyrazine (XX) absorbs at 260m// (e, 6000) and at 327m// (ε 100) in cyclohexane solution, the first band representing benzenoid absorption intensified by two aza-substituents (π -> π*) band and the weak band marking the n -► π*
196
THE ULTRAVIOLET SPECTRA OF NATURAL PRODUCTS TABLE 6.2. PYRAZINES
Compound
u /,Nv
θθΗ JTYY /γγ\> o Η
Bandi
Bandii
Solvent
Reference
327t (100)
260 (6300)
C
(5)
221 (8800) 222 (10,400)
317 (5520) 342 (6200)
pH5 10 N HaS04
(2)
234 (6500)
328 (8300)
A
(6)
480 (20,000)
Ch
(7)
500 (12,000)
Ch
(7)
550 (11,000)
Ch
(7)
363 (40,000)
A
(8)
Aspergillic acid O
t
(YY*) VwV
—
i
o
9 °H
cYn V^N^ t 1
; O
V
O OH
000 T i
—
OHO
CONH2 1
0CÓ t #ι->π* band.
250(120,000)
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
197
transition. Hydroxyl substitution produces the expected wavelength shift, e.g. 2-hydroxypyrazine (XXI) has λΏΙ&χ 317 τημ (ε 5500). 2-Hydroxypyrazine Noxide forms the chromophore of the mould metabolite aspergillic acid (XXII) Nv
/,N.
XX
XXI
o
o
XXII
XXIII
which has Amax 234 and 328 τημ (ε, 6500 and 8300) [cf. 2-hydroxypyridine Noxide (XXIII), ^max 228 and 305 m//]. Dibenzopyrazine-N-oxides occur as elaboration products of certain micro-organisms7. Some representatives of this class are illustrated in Table 6.2. 6.3. PURINES (TABLE 6.3)
Much of the early work devoted to the measurement of the ultraviolet spectra of hydroxyazines and especially the purines, is rendered inaccurate since in adequate control of solvent pH was maintained. As a result, the exact nature of the ionic species under study was often unknown. This situation has now been clarified by the work of Mason9, who has measured a large number of purine spectra using buffered solutions with pH values two units above (or below) the pK of the purine. The λια&χ and intensity values, at appropriate pH, of a selection of purines will be found in Table 6-3.
?Y>
H XXIV
H2N/^\NH? XXVI
XXV
je 2"*
H XXVII
The spectrum of purine (XXIV) (in aqueous solution) is reminiscent of that of pyrimidine. Greater similarity is evident when we compare the spectrum of 2-hydroxypurine with that of 2-hydroxy-4,5-diaminopyrimidine or 2-aminopurine (XXV) and 2,4,5-triaminopurine (XXVI). 2-Hydroxy and 2-amino substituents shift the main band at 260 τημ in both purines and 2,4,5-triaminopyrim-
198
THE ULTRAVIOLET SPECTRA OF NATURAL PRODUCTS TABLE 6.3. ABSORPTION SPECTRA OF PURINES9
Bandi
Compound
^
N
A
N H
3
/
9
ffy
Band II
< 220 (13,000) 260 (6200) < 220 (3000) 263 (7950) 219 (8300) 271 (7600)
264 (4700) 238 (2900) 271 (4800)
322 (6500) 315 (4900) 313 (4800)
pH
0-28 5-7 11
+
-0-75 6-05 10-15
+
-0-75 5-18 10-35
+
OH I 248 (10,500) 249 (10,500) 258(11,000)
H
MeO^
îj/
0
0
0
235 (3240)
280 (10,500) 277(11,000) 285 (12,900)
0 5-4 10-13
+
246 (2600)
284 (6760) 283 (8100) 283 (7600)
0 6 11-4
+
0-20 5-60 11-3
+
H
N/X
Charge of speciest
0
0
OMe 254 (10,000) 252 (9800) 261 (9800)
—
0
H 235 sh 237 sh 236 sh 276 sh
(6500) (4200) (5000) (4100)
325 314 305 303
(4200) (4000) (6020) (5750)
-3-5 1-84 7-0 12-0
++ +
2-1 7 12
+
0
NH 2 1
^ΝΛΝκ H
Adenine
262 (13,200) 260 (13,500) 267 (12,000)
—
0
N-HETERAROMATIC COMPOUNDS (POLYAZINES)
199
TABLE 6.3—(contd.) Compound
NMe 2 |
H
Bandi
Band II
pH
Charge of speciest
+
228 (33,000) 340 (3000) 223 (26,000) 332 (5000) 248 (10,500) 232 (25,000) 327 (4700)
12-7
276 (15,000) 275 (17,800) 221 (16,200) 281 (17,800)
1-7 6-98 13-0
+
1-7 6-98
0
0
OH
HO
/^NAN/
267 (7900) 277 (8300) 283 (8700)
5-05 9-99 13-0
0
240 (8000)
248 (10,700) 246 (10,200) 245 (6000) 221 (13,000)
271 (7100) 275 (7700) 273 (7400) 274 (8700)
1-0 6-2 10-71 13-0
+
OH
H 2 N/
H
0
t 0 Neutral molecule. + + Dication. + Cation. = Dianion. — Anion. idines to over 300 ταμ with a decrease in intensity from the parent value, whilst 6-hydroxy and -amino groups confer a blue shift and intensity increase relative to purine itself. The spectra of purines have two broad bands at 260 and below 220 m//. The 260 τημ band is shifted to longer wavelengths, for a given substituent, in the order 2 > 8 > 6-substituted purine (Table 6.3a). At the same time, the in tensity order for a given substituent is 8 > 6 > 2. Consideration of the avail able data has led to the view that the 260 τημ absorption is a composite band containing contributions from two transitions involving alternative polariz ations within the purine molecule (see XXVII). These polarizations are, re spectively, parallel and transverse to the major longitudinal axis. 8-Substituents exert an effect parallel to the main axis and therefore lower the energy of the stronger component of the 260 πιμ band. 6-Substituents are transversely dis-
200
T H E U L T R A V I O L E T S P E C T R A OF N A T U R A L TABLE 6.3a.
PRODUCTS
SUBSTITUT-TONAL INCREMENTS FOR THE P U R I N E N U C L E U S 9
]Position
Substituent
2
Species
in nucleus
6
8
shift of 260 m/i band (τημ) —NH 2
+
54 42 32
2 -3 -4
28 20 19
—NHMe
+
— — —
7 3 2
36 27 27
+
80 69 56
16 12 10
45 33 35
+
62 52 42
-12 -14 -13
20 14 14
+
24 20 14
-6 -10 -10
— — —
+
— — —
5 -2 0
4 3 3
0 — 0 —
—NMe a
0 —
—OH
0 —
—OMe
0 —
—Me
0 —
posed to this axis and affect the weaker component. Substituents at position-2 are disposed at an angle of 30° to the major axis and appear to affect both band components in shifting the entire band to the red. 2-Substituted purines ex hibit the following order of magnitude in shifting the 260 ιημ band: MeO < MeS < NH2 < HO < NMe2 < HS. The 6-and 8-derivatives show rather variable effects. Tautomerism to pyrimidone forms is marked in the hydroxypurines. For N RO/
-N v
> H
XXVIII
»Yv
HIN/A-NAN/
XXIX
XXX
example, the dissimilarity of the spectra of 2-hydroxy- and 2-methoxypurines (XXVIII; R = H and Me, respectively) and the similarity of the spectra of the amino purine (XXIX) and of its dimethyl derivative (XXX) form sugges tive (but not conclusive) evidence that the hydroxy purines may exist in the lactam form; while the amino compounds again may be considered as true —NH2 compounds.
N-HETEROAROMATIC COMPOUNDS (POLYANZINES)
201
The amino- and hydroxy-purines occur naturally as the bases of the nucleotides. Discussion of structural correlation and diagnosis employing the spectral data of these systems is referred to in Chapter 7 (p. 207).
6.4. PTERIDINES (TABLE 6.4)
Pteridine (XXXI) absorbs at 210,240,300 and 384 ma. The last band (e 80) H
o II
VN
fNìfNH
NAN^
XXXIII
XXXII
XXXI
marks the n -> π* transition and the remaining absorption is naphthalenoid with intensification caused by aza-nitrogen. Thus the 300 ιημ band (ε 7000) is to be compared with the corresponding naphthalene band at 310 τημ (ε 140). The calculated intensity (p. 187) for the 300 τημ band of pteridine is 10,000. The monohydroxypteridines are conveniently divided into two distinct spectral types. The 4- and 7-hydroxypteridines show three bands in neutral TABLE 6.4. PTERTOINES
Compound
8
Solvent
Reference
C
(5)
pH 7 pH13
(10)
375 (6000)
pH7 pH13
(10)
375 (2300)
309 (7800) 271 (4600) 313 (6400)
350 (3000)
pH7 pH13
(10)
230 (9600) 265 (3400) 242 (17,000) 257 (2700)
310 (6200) 333 (6000) 303 (9000)
ρΗ5·6 pH 10 pH 2-5
(10)
Bandi
Bandii
—
300 (7080)
230 (7600) 260 (7000)
307 (6800)
240 (8200) 236 (7800)
311 (7100) 312 (6500)
230 (9400) 236 (6800)
Band III 384 (80)
1
ι Ν ιΓ Ν Me
f^VWe OH
202
THE ULTRAVIOLET SPECTRA OF NATURAL PRODUCTS
solution and their curves are reminiscent of those of hydroxynaphthalenes. 4-Hydroxypteridine is mainly in the pteridone form (XXXII) although there is some evidence from infrared data that hydrogen bonding stabilizes the enol form (XXXIII) to a certain extent. This also is borne out by some similarities in the ultraviolet absorption of (XXXIII) and 4-methoxypteridine (XXXIV). The complexity of such data, however, indicates that we have reached the OMe
0
>NAN^ Me
XXXIV
XXXV
XXXVI
limit of usefulness of the comparison of the spectra of N-Me and O-Me deriv atives for purposes of assessing equilibria. The spectrum of 7-hydroxypteridine (XXXV) is, however, so similar to that of the pteridone (XXXVI) that the keto form is almost certainly preferred. It must be mentioned that the infrared specI tra of all hydroxypteridines show strong — C = 0 bands at 1670-90 cm * in the solid state. OH
- ίΝιΛ«
H
Yìf»
H XXXVII
XXXVIII
XXXIX
The 2-hydroxypteridines represent another category of pteridine spectra. Their absorption curves are complicated by reversible hydrate formation (XXXVII ^ XXXVIII). This is also true for 6-hydroxypteridine (XXXIX) which absorbs in the infrared at 1690 cm"1 and, Hke the 2-isomer, gives a two banded spectrum. Riboflavin (XL) contains the quinomethine chromophore of the pteridine nucleus within a tricyclic framework. The long wavelength band of riboflavin responsible for its colour occurs11 at 445 τημ (pH l). CH^CHOH^CHisOH
o XL
Riboflavin A 445 τημ
N-HETEROAROMATIC COMPOUNDS (POLYAZINES)
203
REFERENCES 1. S.F.MASON, / . Chem. Soc, 1247 (1959). 2. S.F.MASON, ibid., 1253 (1959). 3. J.R.MARSHALL and J.WALKER, ibid., 1004 (1951).
4. D.J.BROWN and L.N.SHORT, ibid., 331 (1953). 5. S.F.MASON, Chem. Soc. Special Publications, 3, 139 (1955). 6. G . D U N N , J.J.GALLAGHER, G.T.NEWBOLD and F.S.SPRING, / . Chem. Soc, 5126 (1949).
7. G.R.CLEMO and H.MCILWAIN, ibid., 479 (1938).
8. L.BIRHOFER, Ber. dtsch. ehem. Ges., 85, 1023 (1952). 9. S.F.MASON, / . Chem. Soc, 2071 (1954). 10. D.J.BROWN and S.F.MASON, ibid., 3443 (1956). 11. R.M.CRESSWELL, A . C . H I L L and H . C . S . W O O D , ibid., 698 (1959).