CHi\PTER -VI
STUDY OF REACTION PRODUCTS 21b
Introduction
Vie may recall the difference of behaviours obtained in the repetition of the reaction of sodium salts of salicylamlde with DNCB in methanol and DMSO mentioned earlier.
In alcohol, the reaction led to a quantitative yield of the
N-substituted derivative while in DMSO the reaction took a more complicated course giving an interesting display of colours.
This strongly suggested that the nature of the reactive intermediate was affected by solvents. It was this observation that first suggested the possibility of tautomerism in the anions of o-hydroxyarylamides. From both spectroscopic studies and ionization constant measurements, it has become clear that such a tautomerism does exist. It would be of interest to find out how this tautomerism would affect the course of reaction in both the solvents. This detailed study of reaction products would also enable one to work out the best reaction conditions for the kinetic study which is dealt with in the next Chapter. It was of interest, in this connection, to obtain the comparative behaviour of the p-hydroxy isomers as well. Thus, the compounds investigated included p-hydroxybenzamide, p-hydroxybenzanilide, salicylamide, salicylanilide, Bon acid amide, Bon acid anilide and salicyl 2 ’ 5^-'-dinitroanilide.
Results and discussion
The reaction of p-hydroxybenzamide and p-hydroxybenzanilide 2iy
with DNGB in the presence of base in alcoholic solvents led to the formation of dinitrophenyl ethers. Due to the solvolysis of these salts, small amounts of dinitroaryl ethers were also Isolated. Under the conditions employed for this reaction these XiTere of the order of 2 to of the total yield v/hen more than S5% of the reaction was over. The
2 ' , -dinitrophenyl ethers of the compounds were stable and could be easily identified from their NMR spectrum.
In the case of the o-isomers like salicylamide, salicylanilide, Bon acid amide and Bon acid anilide, the reaction with DNGB in ethyl alcohol led exclusively to the formation of N-2', -dinitrophenylamides in near quantitative yields. No dinitrophenetole could be isolated in the reaction mixture under the conditions employed for the reaction. 1 I Small amounts of cleavage products from the N-2,4—dinitrophenyl derivatives, the corresponding ethyl ester of the acid and substituted anilines, were,however, isolated. These were of the order of only 2-3% of the total reaction. The ethoxide ions formed by solvolysis apparently preferred to attack the product anilide rather than DNGB. The recognition of this minor side reaction was actually helpful in explaining the drifts from bimolecular kinetics observed in later experiments.
Taking the specific case of the sodium salt of salicylamide, reactions were carried out under different concentrations in methanol and ethanol. In methanol, the 22 0
solvolysis and cleavage were more than in ethanol. This was in accordance with the fact that EtO® is a stronger base than MeO®.
1 1 The pure 2 , dinitroanilide had a characteristic NMR spectrum (F ig .l). The -H absorption was at the lowest field compared to all other aromatic protons probably because of the intramolecular hydrogen bonding of the NH to the ortho nitro group and the influence of the deshielding effect of the suitably orienting C=0 group. This was followed by the signals of and -H protons oil the high field side. The salicyl protons were seen next. The splitting patterns were similar to that of the aromatic protons in salicylamide.
The OH and NH were seen clearly at 7^^ and 712 Hz respectively.
It is of interest to note that the dinitrophenyl ether of salicylamide prepared from the dinitrophenyl ether of methyl salicylate according to the procedure of Tozer and
Smiles^ had a very different NMR spectrum in the same solvent
(DMSO) (F ig .l), In the spectrum of the 0-dinitrophenyl derivative -H and C^’ -H protons were at low field followed by the salicyl aromatic protons. These were closely packed compared to the pattern observed in salicyl 2 ' , -dinitroanilide,
The Gg,-H was at the highest field. The change of position of -H from the 0- to N-substituted derivative was dramatic. 22 i o
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UJ X u . Q_ o 0 q ; < H or h - Z u Q liJ 1 Q- {/) V "c\j X o O li. 2 2 2 When salicyl-2’ , -dlnitroanilide was treated with DNCB in the presence of base in methanol, the reaction was slow. The characteristic smell of methyl salicylate was obtained indicating cleavage. The main products other than the reactants isolated were 2,^--dinitroaniline, 2,^—dinitro- anisole and methyl salicylate. It was clear that the amide salt was giving rise to free methoxide ions on accoimt of solvolysis and these were cleaving the amide to methyl salicylate and 2 , dinitroaniline, and also simultaneously reacting with DNCB to give dinitroanisole. No further substitution of the nitrogen had taken place. Attempts that were made to trace the course of the reactions that take place in DMSO have yielded only limited information. The only reaction which was taken up for a detailed study was that of salicylamide salt with DNCB. It was clear that the first stage in this case was the formation of N-dinitrophenyl derivative. As seen from the details in the experimental section, it was this product that reacted further with DNCB so that for following the transformations that took place later, it was better to start with the anilide salt and DNCB. The reaction was arrested at the stage when the solution was dark green and an attempt was made to analyse the components of the mixture obtained by a combination of coliamn and thin layer chromatographic techniques. This attempt was only partially successful because of the closeness of values of the numerous and strongly coloured products. T l ^ Some of the compounds that could be Identified were 2,^—dlnitroanlline, 2 ,!+-dinitrophenyl ether of salicyloyl- salicyl-2'-dinitroanilide (i.e. a diplosal derivative) and 2,^-dinitrophenol. Perhaps, it is the isolation of the dinitrophenol that deserves most of the comments here. Since the reaction mixture was quenched with dilute acid, it could not have arisen on account of hydrolysis of the unreacted amide salt and subsequent reaction of OH ions with DNCB during work-up. Actually, the isolation of unreacted anilide and DNCB itself is anamolous in the sense the initial reaction was found to be vigorous giving a moderate heat output. The implication seems to be that the dinitrophenol and the unreacted anilide are probably decomposition products of the imino-ether (I) which can conceivably be formed under the reaction conditions. A similar reaction does not take place in alcohol. The amidate ion in alcohol is apparently not reactive enough in the required mode. NO 2 r \ NO2 2 ‘> J The probable structure (II) of the compound that has been characterized as a diplosal derivative is as shovm in (F ig .2 ). Although NMR studies showed the amidate form to be H 21 predominant even in DMSO, the presence of the phenolate-amide form or phenolate-imlne-ol form is actually implied by the formation of dinitrophenyl ether (III). Further attack on (I I I ) at the carbonyl group by the amide anion can result in the formation of the observed product. In this case, dinitroanilin© should be a product. Since this has been isolated jit may be presumed that this is the path by which (II) is formed. It would appear that there is nothing to stop (II) from undergoing further reactions of the same type to give even larger molecular weight compounds. This possibility would account for the occurance of diplosal type of derivatives with a higher salicyl content among the products as has been observed. © 2‘2 5 N o 1 tsj ) X II - o o E _J > - 1 5 o UJ '-4 _J / T“ \ < < I O in u - O in i OJ \ l l 0 q: LU 1 I— L UJ I _J >• z. LU X Q- O O 9^ u) h- \ X Q Q ;^ — ^ 9 ) ro . ' UJ OJ Q o T — (X) U . □ K O i ^ < D o q: q ; h- I- sr o UJ Q CL CO I V q : 2 "c\J ^ _J N > - X u a. Z) o < o (T> CO cr o (\J >- 2 O LU X U. a o a: z Q 2 2 ( ' Conclusions The reactions of the amide salts with DNCB in methanol gave fairly clean results. Side reactions were very minor and the substituted amides were the main products. In an attempt to trace the course of the reactions between the same reagents in DMSO, 2 ,^-dinitrophenol and a biz-dinitrophenyl derivative of diplosal amide were isolated. The phenol formation has been rationlized in terms of the formation of an imino-ether from phenol-amidate form of the amide salt. 2 2 1 EXPERIMENTAL Reaction of o- and p-hydroxyamlde anions with DNCB in EtOH at ^-0°C. The reaction of the sodium salt of salicylamide with DNCB in EtOH at is described in detail. A similar procedure was adopted for all other compounds. The data for all the reactions, the products isolated, percentage of cleavage of the final product and percentage of side reaction arising due to solvolysis are indicated in Table I. The substrate amides were prepared and purified according to the procedures given in Chapters II and III. They were further dried at 80° under vacuum for two to three hours. To salicylamide (0 .27^- g) taken in a round bottomed flask an equivalent amount of sodium methoxide in methanol was added. The excess methanol was stripped under vacuum and ethanol (2 ml) was added to the dry salt to give 1.0 M solution. A 0 .5 M solution of DNCB in ethanol was prepared by dissolving 0.2025 g of it in 2 ml of the solvent. Both the solutions were mixed well and the reaction flask kept stoppered in a thermostat at ^-0° for four hours. The reaction mixture was quenched with 5 ml of IN nitric acid, diluted, transferred to a separating funnel and extracted with ethyl-acetate. The aqueous layer was withdrawn to a beaker. The ethyl-acetate layer was washed successively with water and the aqueous layer was further 2 2 b tiOCP c\i >d Q) o o •H -P CO CO tH O W CM O nj fnCD 'aCP c: • H o CO -H ro (XI -PO O cu CO ■T3 s s s S + J CD O -P (X! vD rO ITN vO CO ^3 rf tN- CXI (XI J - ro rxi -13 rH [>- l>- O 00 00 O ^ 1—1 H 1—i H 1—1 r -{ ? H CO •• • • •» a, -H O O O O O o M I a o O -H I—ICD •H-P +rj J O fH 05 CO -P fri CD -H 00 lr\ o 00 -P CN CO C« CO o e o • •• •• • o (H CVl o n lr\ vD 2 2 ii extracted with ethyl acetate twice so as to ensure complete extraction of the organic material. The ethyl acetate layer was dried over anhydrous sodium sulphate and stripped at low temperature ^-O^C) to yield a yellow solid ( 0 A 05 g). The aqueous layers were mixed and a chloride estimation was done by titrating it against standard silver nitrate solution in an automatic titrimeter. The chloride estimation in this case yielded 77.6^ reaction. The yellow solid was loaded in a column containing silica gel in pet-ether and was eluted initially with a mixture of 50% pet-ether-benzene mixture and later with benzene and chloroform. The compounds isolated were (i) unreacted DNCB (0,0602 g), (ii) unreacted salicylamide (0,1668 g), (iii) salicyl-2', -dinitroanilide (0.2202 g), (iv) 2,i+-dinitro- aniline and ethyl salicylate (0.0189 g). In short, the anilide yield was close to quantitative, and it was in agreement with the chloride estimated. The order of cleavage was only 3?^^. No dinitro phenetole could be isolated. In the case of the p-isomers both DNCB and sodium salt of p-hydroxybenzanilide were taken in the molar concentrations of 0,5m . p-Hydroxybenzamide sodium salt had limited solubility and hence the reaction was done with 0,25 M solutions, In these cases^small amounts of dinitrophenetole were isolated. 2:^0 There was no complication arising due to cleavage of the final product since these dinitrophenyl ethers were quite stable. Reaction of sodium salt of 2' , -dinitrosalicylanilide with DHCB in MeOH, The reaction of sodium salt of salicyl 2 ' -dinitro anilide (0.2^-3^ g) and DNCB (0.1526 g) was done as in the above case in MeOH. Towards the end it^was gently warmed on the water-bath for 1-2 hrs. Needle shaped crystals started precipitating. These were filtered off, methanol stripped and the solid adsorbed in silica gel and loaded on a column packed with the same material. The elution was done as before, The main products isolated were 2 ,H-dinitroaniline, 2,^- dinitroanisole and methyl salicylate. Some unreacted DNCB and salicyl 2 ' , -dinitroanilide were also obtained. Reactions of sodium salts of salicylamide and salicyl 2 ’ , -dinitroanilide with DNCB in DMF, DMSO and acetone. When the sodium salt of salicylamide dissolved in DMSO in a round bottomed flask was reacted with DNCB in DMSO the colour of the solution was initially red which became darker in an hour’ s time and within 2-3 hrs it became bright green. VJhen the flask was kept tightly stoppered; it was green for about ten days and after that it slowly reverted back to red colour. But, when the mixture was kept open, 2 : a the red colour appeared v/ithin four days with deposition of some white material. In DMF, this colour change was faster v/hile in acetone it was relatively slow. The TLC of the reaction mixture showed a large number of yellow spots with very close r^ values. It was suspected that the reaction was not stopping with the initial formation of salicyl 2’ ,^-'- anilide, So when the reaction was repeated with sodium salt of salicyl 2',*+'-dinitroanilide, the same array of colours was was obtained. Therefore it/decided that it would be better to study the reaction of sodim salt of salicyl 2', >+'-dinitroanilide (instead of that of salicylamide) with DNCB. Hence the reaction was repeated with 0.606 g of sodium salt of salicyl 2', i+’-dinitroanilide and was worked up after reaching the green stage. The reaction mixture was acidified and diluted with water. The solution turned brownish yellow with small crystals floating in the oily solution. It was extracted with ethyl acetate and the aqueous solution was estimated by chloride titration. The percentage of reaction was 78!?. ,got A TLC of the mixture of products/by stripping the ethyl acetate showed a number of strongly coloured yellow and pink bands with very close r^ values. It was clear that separation of the constituents would be difficult. A part of the solid was separated by column chromatography and further by preparatory thin layer chromatographic techniques. Even this yielded only crude separation and hence repeated thin 2", 2 layer chromatographic techniques were tried in various solvent combinations to get at least some pure constituents, Those ■;h;'.ch coulci be identified were (i) unreacted DNCB (0.098 g), (ii) unreacted salicyl 2', -dinitroanilide (0.160 g), (iii) dinitroaniline (0.0128 g) and (iv) dinitrophenol (0„050^- g). The substances were identified by their mass and pmr spectra. The reaction mixture also yielded some colour compounds with strong yellow/which gave complex spectra. The spectra indicated the presence of compounds with at least two dinitrophenyl groups in different environments and also varying numbers of salicyl residues. Working out the integral ratios in detail, they were assigned diplosal type of structures. One of them ( 0.1303 g) gave a mass spectrum which did not give a molecular ion peak. There were strong peaks at m/e 303, m/e 183 and m/e 120. A reference fragmenta tion pattern of 2 ' , -dinitrophenyl ether of salicylic acid showrd a molecular ion peak at 303. Wiih sueee»^4ve also a dinitrophoRr^^y It^gave peaks at m/e 183 and m/e 120. This confirmed the structure of the above compound as (IV). The main fragmentation mode of IV is indicated by a dotted line in the following structure. 2 '.;> The presence of other compounds of the same type was Indicated by the NMR spectra of some of the fractions. These showed a higher salicyl content suggesting the possibility of structures like ( '/). NO2 ( n = 1,2,3^---) There were a few very small fractions out of which two wei-e pink. No information on their structures could be obtained from their NMR spectra which gave very broad signals, It appeared likely that the samples were paramagnetic. References 1. B.T. Tozer and S. Smiles, J.Ghem.Soc.. 2052 (1938),