[CONTRIBUTION FROM T H E WELLCOME
RESEARCH LABORATORIES]
CONDENSATION OF AROMATIC ALDEHYDES WITH a-PICOLINE METHIODIDE ARTHUR P. PHILLIPS Received November 4 , 1946
Styryl derivatives of pyridine and quinoline and their methiodides can serve as useful intermediates in the preparation of types of compounds known to possess valuable pharmacological properties. Some of the methiodides are known to be powerful photosensitizers for light of certain wave lengths. A series of 2-styrylpyridine methiodides has been made for pharmacological examination, and some correlations have been noted between the colors of the products, the yields obtained, and the substituents on the nucleus of the aldehyde reactants. It has long been recognized that substituents in the 2 or 4 position of pyridine and quinoline rings were subject t o the same type of activation as occurs with similar substituentswhen located either ortho or para to nitro groups on a benzene ring. Thus 2- or 4-methylpyridines or quinolines, or 0- or p-nitrotoluenes can be made to condense with aromatic aldehydes to give stilbene-like products. These condensations usually require strenuous dehydrating conditions and frequently give poor yields. Kaufmann and Vallette (1) reported the observation that the methiodides of these methylpyridines and quinolines react more readily and under milder reaction conditions than the tertiary bases. Thus, although no condensation was obtained between p-nitrosodimethylaniline and quinaldine, lepidine, or a-picoline by heating at elevated temperatures, the methiodides of the heterocyclic bases reacted with the nitroso compound rapidly in alcohol solution, even a t room temperature, piperidine being used as a condensing agent. Recently Koelsch (2) reported the preparation of four a-stilbazole methiodides and summarized the few instances of prior work in this line. Koelsch condensed his aldehyde reactants with equimolecular amounts of a-picoline methiodide in alcohol solution at room temperature with a trace of piperidine as catalyst. In this work, the preparative procedure chosen was a modification of that of Koelsch. An excess of aromatic aldehyde (13 to 2 moles of aldehyde per mole of a-picoline methiodide) was used to make it more likely that any unreacted starting material would be the aldehyde, as this should be more readily separable from the salt-like product than a-picoline methiodide. The catalyst piperidine was used in larger amounts (about 4 mole piperidine per mole of a-picoline methiodide) and the reaction mixtures were refluxed for periods of from one to four hours. Repetition of some of Koelsch’s preparations under our conditions led to greater yields more rapidly obtained. EXPERIMENTAL
All melting points are uncorrected. Prtyaration of the stilbazole methiodides. Five grams (0.021 M ) of a-picoline methiodide and 5 g. (0.03-0.04 M ) of the aldehyde to be condensed were mixed and diwolved in 25-30 333
334
ARTHUR P. PHILLIPS
nMHa
TABLE I DERIVATIVES OF a-Stilbazole METHIODIDE
R
N\ cH3 I
Ri
/
ANALYSIS
COKP'D NO.
iUBSTITUENTS ON BENZENE XING
-C H -
I I1 111 IV V VI VI1 VI11 IX
x XI XI1 XI11 XIV
xv
XVI XVII XVIIE
ABSOXPTION LAXIMUM,
Found
Calc'd
M.P.,T.
C
H
A
230-231 263-264 228-229 293-294 258-260 242-%3 253-254 221-222 269-270
73 65 63 72 85 92 82 92 70
52.00 53.40 46.98 46.98 45.64 50.98 49.54 49.54 49.54
4.37 4.78 3.66 3.66 3.56 4.57 4.16 4.16 4.16
-51.95 4.45 3340 53.33 4.60 47.10 3.66 47.00 3.81 45.56 3.76 50.70 4.34 3590 49.60 4.38 49.49 3.90 49.29 3.88 3630 4350d
295
70
49.03
3.84
49.08 4.02
3,4-(CH30-):! 2,5-(CHoO-):: 3-CHs0-4-KO3-C*H60-4-H02-HO-3-CzHsO3,4-(HO-)e 4-(CHa)zN-'
244-245 244-245 275-276 260-261 242-243 270-271 273-274
88 88 83 88 83 40 97
50.12 50.12 48.77 50.12 50.12 47.31 52.43
4.72 4.72 4.36 4.72 4.72 3.97 5.24
50.23 50.29 48.77 50.08 50.20 47.60 52.48
4-(CHa)sN-#
272-273
67
40.14
4.37
39.93 4.31
232-233 246-247
73 95
43.13 54.79
4.09 42.94 3.99 5.88 54.68 6.05
Nonea 4-CH3 2-c13-C13-NO,-' 4-CHsO-' 2-HO3-HO4-HO-c
/
3,4-C11202
\
4.89 4.96 4.61 4.99 4.88 4.58 5.20
3270b
4440b 3230f 3200
\
XIX
xx
I 3-Br-4-(CH&N4-(CnHs)eN-
3600
0 Koeniga, Kijhler, and Blindow [Ber., 68,933 (1925)l have reported this compound, but give its melting point as 215216". * Absorption spectrum of a 0.0013oJo solution in distilled water. c Previously described by Koelsch, reference (2). d Absorption spectrum of O.ooOs6% solution in 0.1 N sodium hydroxide. e Previously described by Mills and Pope, reference (5). Absorption spectrum of 0.00066% solution in 0.1 N hydrochloric acid. 0 This product made in two ways as described in text. The yield reported here is t h a t obtained from reaction of the quaternary iodide of the aldehyde witha-picoline methiodide.
cc. of absolute methanol. Piperidine (1 cc.) was added and the reaction mixture was refluxed o n the steam-bath for a period of from one t o four hours, or until bumping from precipitated solid became prohibitive. After cooling, the solid was collected, washed with
CONDENSATIONS WITH (r-PICOLIKE METHIODIDE
335
and recrystallized from methanol. In a number of cases, the results of which are the basis for some discussion, preparations were run in duplicate. Yields reported are those of product crystallized once from methanol. Sometimes the first crop of crystals obtained from the reaction mixture represented only a fraction of the total yield, and in these cases the mother liquors were evaporated t o a small volume to obtain a second crop. The combined crops were then recrystallized from methanol to obtain the reported yield. The results are shown in Table I . Alternative preparation of XVZZZ. p-Dimethylamino-a-styrylpyridine methiodide (XVII) (1.2 9.) was mixed with 5 cc. of methyl iodide in 25 cc. of methanol and the mixture was refluxed for 10 hours. Partial evaporation of the solvent, followed by cooling, yielded 1.O g. (50-6077,) of yellow-orange crystals. After crystallization from methanol the product melted at 272-273", and was identical with the material obtained from condensation of a-picoline methiodide with the methiodide of p-dimethylaminobenzaldehyde. The melting of this compound seems to involve a gradual reversion t o the more stable structure XVII by the loss of methyl iodide, for the color undergoes a change from yellow-orange to deep red as the temperature is raised, and the final melting point, with decomposition, is identical with that of XVII. Absorption spectra. Absorption spectra of a few of the representative types were taken t o give a more precise basis for some of the discussion. The absorption curvea for these compounds are very much the same in general shape, showing intense absorption in the ultraviolet and one characteristic peak, varying in intensity and exact location with the individual compounds, but lying in or near the visible portion of :he spectrum. The absorption maxima of compounds I (3340 A), XI1 (3270 A), XVII in acid solution (3230 A), and XVIII (3200 1)were taken as a rough indication of the probable location of the maxima for most of the other substituted compounds, which would not be expected t o possess the more powerful resonance effects.
Acknowledgment. The author is happy to express his gratitude to Mr. Samuel W. Blackman for the analytical results reported here, to Mr. Walter S. Ide for the absorption spectra obtained, and to Dr. Richard EaltPly for his continued interest and advice. DISCUSSION
A. Color. As would be predicted on the basis of the theory of color outlined by Lewis and Calvin (3), the a-stilbazole methiodides were colored, though except for the dialkylamino compounds all were of varying shades of yellow. The p-dimethylamino and p-diethylamino derivatives, however, were a bright purple-red color. This marked deepening of color with the latter compounds is attributed to the increase in intensity of light absorption and the displacement of the absorption maxima to longer wave lengths consequent upon the greater mobility of electrons of the chromophoric system stimulated by the additional important contribution of resonance forms of type A(b) to the classical structure A(a).
R (a) XVII R = CHa XX R CzHs (bright red; R = CHJ abs. max. 4440 A)
336
ARTHUR P. PHILLIPS
CH,
(b) (yellow; abs. msx. 3340 A)
Resonance forms of the type I(b) should differ widely in energy content from the classical structure I(a), and thus would be expected to contribute relatively weakly to the total structure of the molecule, or to its light absorption characteristics. 'The energy contents of the resonance forms A(a) and A(b) should be much more nearly equal, and A(b) would therefore be expected to participate to a much greater extent in the over-all structure of the molecule. In harmony with both theory and facts, the presence of the strong basic auxochrome facilitates and intensifies the absorption of light as compared with the unsubstituted molecule I. That resonance forms of the type shown in A(b) are important in color production in the molecule is indicated by the fact that the addition of dilute hydrochloric acid to the highly colored compound, in water, produces a colorless solution. When the p-dialkylamino group on the benzene ring is tied up as the hydrochloride A(c) , the valence requirements of this nitrogen are completely fulfilled, and having no unshared electron pairs it can no longer enter into important resonance structures such as A(b). Addition of alkali restores the original deep red color.
A (colorless; R =
(4
CH3,
abs. max. 3230
A)
Two other methods were used to test the hypothesis that interference with the resonance forms A(b) would decrease or destroy the color of the molecule: (I) The bis-methiodide XVIII corresponding t o XVII was made by two methods :
CONDENSATIONS WITH a-PICOLIKE METHIODIDE
XVII
+
CHaI
-+
337
XVIII (pale yellow; abs. max. 3200 A)
In this case, as with the hydrochloride A(c), the p-nitrogen on the phenyl is saturated, in the form of its quaternary salt, and can no longer give rise t o such structures as A(b). The product XVIII has a pale yellow color with its characteristic absorption maximum a t 3200 as compared with the maximum at 4440 for compound XVII. Its maximum lies at significantly shorter wave lengths even than that of I (3340 A), and this can be explained, possibly, as the repression of the weak resonance forms of type I(b) by the presence of the strong cation in the para position of the benzene ring. (11) Introduction of a large atom or group into one or both of the positions adjacent to the dimethylamino group should, by steric hindrance, mechanically interfere with the coplanarity of the dimethylamino group and the benzene ring, thereby cutting down or eliminating completely the participation of the A(b) type of resonance.
+
CHJ
O C H a - - N
-
/ \
CIIJ
I
\ Br
/ \
MeOH Piperidine4
CH3
XIX (light orange; abs. max.
$600 A)
Bromination of p-dimethylaminobenzaldehyde gave m-bromo-p-dimethylaminobenzaldehyde, which upon condensation with a-picoline metohiodide gave XIX. This product was light orange in color (abs. max. 3600 A) indicating
338
ARTHUR P. PHILLIPS
that by the device being tested here resonance of the A(b) type is inhibited considerably but not completely eliminated. Cocker and Turner (4) have prepared the m-dimethylamino- and m-diethylamino-stilbazole methiodides and described them as orange or orange-red crystals, giving orange colored solutions. They also report the discharge of the color of their products by acids and restoration by alkali. Thus, dialkylamino groups, even in the meta position, can serve as auxochromic groups, although the A(b) resonance structures are not possible for them. Since the absorption data are not available, it is impossible to compare precisely the positions and intensities of the maxima for these substances with those of XVII. But from the color description afforded one might place the absorption maxima of the m-derivatives a t about 3600-3800 8. Certainly from theoretical considerations the characteristic maxima should fall a t markedly shorter wave lengths than for the para analogs. Also the shift in the position of the maxima for the meta compounds, on addition of acid, should cover a much narrower range than with the para derivatives. More evidence may be presented on this point a t a later
date. The hydroxystilbazole methiodides offer another good opportunity for the correlation of color with the possibility of important resonating ionic structures.
Ix
/\
/\
+--+ [ N , J = c H - c H < ~ ~=/ H
j ! J - - c ~ = C H - - < ~ - o--H
/+ CH,
I
(a)
(yellow; abs. Max. 3630
a)
CHI (b)
When the hydroxyl group if located in the 0- or p - positions resonance forms such as IX(b) can be written. However, the energy contents of the (a) and (b) forms of I X should not be as nearly the same as \\-ere the (a) and (b) forms of A. Thus, the contributions t o the structure and color of the molecule should be much less with IX(b) than was the case with A(b). In agreement with these expectations the hydroxystilbazoles were all pale yellow and for I X the absorption maximum was a t 3630 8. In alkaline solution, however, other resonance forms are possible [IX(c) and IX(d)] in which the energy contents of the two principal resonating structures should be more nearly the same and these forms should be of marked influence on the color and structure of the compound.
/\
/\
IX (N)-CH=CH-
