Chemical Evidence

Acetamidothiazole and its 4-alkyl derivatives react with chloro-sulfonic acid. The structure of the resulting products was a subject of controversy (172. 393-397). N-acetyl-A -(2-thiazolyl)-sulfamoyl chlorides (189) first proposed were then shown to be 2-acetamido-5-chloro-sulfonylthiazoles (190) (Scheme 120) (367. 368. 398). the latter assignment is based on infrared (368) and chemical evidence (367). 

Chemical Evidence for PX Monomer. Estabhshing early on that PX is indeed the pyrolysis product, rather than the molecule formed by breaking only one of the original diben2yl bonds, the dimer diradical (5), would prove to be an important development. 

It was previously bebeved to be a peroxide, but chemical evidence has ruled out this possibiUty. The most likely formula of this diamagnetic material is... 

Calculated rr-bond orders are summarized in Table 1. These calculations are supported by chemical evidence that the S—N bond is the one most easily cleaved. Attempts have been made to relate bond orders and electron densities to NMR coupling constants (74CJC833, 77aC6i9> and CNMR (75CJC596, 75CJC1677> and NNMR (78JOC4693> chemical shifts, with limited success. 

IP, isolated pure MI, matrix isolated GP, data from pure gas phase material CE, chemical evidence for existence TH, theoretical calculation XR, X-ray structure MW, microwave structure UV ultraviolet spectrum. 

It was agreed at the workshop that endocrine disrupting activity could only be adequately defined in terms of effects in intact animals, be they juvenile or adult, or in the offspring of exposed parents. For many chemicals, evidence of endocrine disrupting activity has been obtained only by the use of in vitro models, such as hormone binding assays. It was accepted, therefore, that chemicals active in such models should be considered only as potential EDs and should be distinguished from those established as active in vivo. For such chemicals, an alternative definition was recommended ... 

It is of interest to note that rhyncophylline occurs in two genera, Mitragyna and Ourouparia. Raymond-Hamet suggested in 1936 that rhyncophylline, hanadamine and formosanine are chemically and pharmacologically related to the Mitragyna alkaloids and the first chemical evidence of this is the identification of mitrinermine with rhyncophylline (Barger et al.). Millat has recently expressed doubt of this identification. 

In addition to the expected 2,2-dimethyl- and 2a-methyl- compounds (7) and (8) the 2 -methyl-3-ketone (9) is obtained. Chemical evidence and optical rotatory dispersion measurements indicate that ring A in (7) and (9) is in the boat conformation. 

Until the second half of the twentieth century, the structure of a substance—a newly discovered natural product, for example—was determined using information obtained from chemical reactions. This information included the identification of functional groups by chemical tests, along with the results of experiments in which the substance was broken down into smaller, more readily identifiable fragments. Typical of this approach is the demonstration of the presence of a double bond in an alkene by catalytic hydrogenation and subsequent determination of its location by ozonolysis. After-considering all the available chemical evidence, the chemist proposed a candidate structure (or structures) consistent with the observations. Proof of structure was provided either by converting the substance to some already known compound or by an independent synthesis. 

The Chemical Evidence for the Schiff Base Intermediate in Class I Aldolases... 

Fructose bisphosphate aldolase of animal muscle is a Class I aldolase, which forms a Schiff base or imme intermediate between the substrate (fructose-1,6-bisP or dihydroxyacetone-P) and a lysine amino group at the enzyme active site. The chemical evidence for this intermediate comes from studies with the aldolase and the reducing agent sodium borohydride, NaBH4. Incubation of fructose bisphosphate aldolase with dihydroxyacetone-P and NaBH4 inactivates the enzyme. Interestingly, no inactivation is observed if NaBH4 is added to the enzyme in the absence of substrate. 

Physical and chemical evidence supporting the theory mentioned in the foregoing will be given in the appropriate sections. Some predic-. tions may be mentioned here. From resonance structures (2, 3, 7, 8) it is inferred that the substituent effect in 2-substituted thiophenes should be parallel to that in the corresponding benzenes, the 3- and 5-positions may be considered as ortho and para positions and the 4-position as a meta position. It is, however, obvious that the effect of a —M- and a d-M-substituent are not simply reversed, as reso-... 

Tautomerism can be studied by various chemical and physical techniques, In principle, it is possible to obtain significant results from chemical evidence, but in practice this is very difficult, and physical methods are much more useful. Chemical methods are discussed first and emphasis is placed on the dangers inherent in their application. It... 

Methods of the first type have been used for both qualitative and quantitative investigation. An important limitation is that the rates of interconversion of the tautomeric forms must be small as compared with those of the test reaction (s). The method is further complicated since the test reactions are sometimes complex and it is difficult to be certain that only one tautomer is reacting. An even more fundamental objection is that much chemical evidence is based on incorrect reaction mechanisms. Thus, the formation of condensation products (30) with aldehydes has repeatedly been quoted as evidence for structures of type 31 and against type 32,. whereas if 31 does react with an aldehyde it must either first tautomerize to 32 or ionize to 33. 

Hydroxyisoquinolines have been considered to exist as such rather than as 30 on the basis of chemical evidence, and, indeed, the infrared spectrum of this compound was reported to show a v OH band at 2.93/j(, (3413 cm ). These results have been questioned, the iso-... 

Phthalic hydrazide has received even more attention than maleic hydrazide, the potential tautomerism having been discussed since 1925. Chemical evidence has been advanced both for the dioxo form and for the dihydroxy form 89, and it has been fur-... 

Early investigators adduced various kinds of chemical evidence in support of a monohydroxy-dioxo structure for barbituric acid (112) (a) reaction with diazomethane afforded a mono-O-methyl deriva- iye,i59,i6o barbituric acid and its 5-alkyl derivatives are much stronger acids than the 5,5-dialkyl derivatives, and (c) the 5-bromo and 5,5-dibromo derivatives have different chemical properties. - The early physical evidence also appeared to substantiate the monoenol structure, this formulation having been suggested for barbituric acid in 1926 on the basis of its ultraviolet spectrum and again in 1934, In the 1940 s, ultraviolet spectroscopic studies led to the suggestion of other monohydroxy and dihydroxy structures for barbituric acid, whereas its monoanion was assigned structure 113 (a clear distinction between ionization and tautomerism was not made in these papers). 

Tanner,from infrared spectral work, tentatively concluded that 4,6- and 4,5-dihydroxy- and 4,5,6-trihydroxy-pyrimidines exist in the monooxo forms 117, 118 (X = H), and 118 (X — OH), respectively these conclusions are supported by ultraviolet spectral data and chemical evidence. " 2,4,5,6-Tetrahydroxypyrimidine has been isolated in two forms—dialuric acid and isodialuric acid, usually formulated as 119 and 120, respectively, on the basis of rather convincing chemical evidence [for a review see reference 109(f) cf. reference 178]. Isodialuric acid is converted into dialuric acid by base as would be expected if structures 119 and 120 are correct. On the basis of its infrared spectrum, dialuric acid has been concluded to exist in the tetrahydroxy form, but the correctness of this conclusion appears very doubtful. 

Dimethylquinoxaline (303) has been reported to undergo a Diels-Alder reaction with maleic anhydride to give 304, 305 having been postulated to be the reactive form. However, attempted confirmation of this unexpected result has shown that 304 is not the correct structure of the reaction product. " In 1931, other chemical evidence was advanced in support of structure 305,but it would no longer be considered valid. 

Dinitrobenzofuroxan dissolves slightly in water, giving an acid reaction, and forms a series of explosive - salts which were originally formulated as containing the anion (54). Acidification regenerates the dinitro compound. It has recently been shown that the anion is, in fact, the Meisenheimer-complex (55), on infrared, NMR, and chemical evidence, including the use of 0 and... 

From 4-phenylthiosemicarbazide Freund and HempeH obtained a product to which they assigned the structure of a tetrazolinethione. When heated in alkaline solution it was isomerized to a compound which, on the basis of adequate chemical evidence, was considered to be 5-mercapto-l-phenyltetrazole. According to Lieber and Ramach-andran, however, the initial product is 5-phenylamino-l,2,3,4-thia-triazole. Lieber and Slutkin have also converted some di(thiosemi-... 

The thiatriazoles are recovered quantitatively and unchanged after treatment with hydrogen sulfide. This is convincing chemical evidence against the thioazide formulation. 

Chemical evidence led to the conclusion that the conjugate acids of pyrrole probably exist predominantly as 16 or 17 rather than as X52,4,5 Although infrared spectra were initially interpreted on the... 

Very little is known concerning the simple, monocyclic 3-hydroxy-furans (cf. reference 15). Both the oxo and hydroxy forms of the substituted 3-hydroxyfurans 26 and 27 (R = H, CcHn) have been isolated/ but the individual tautomers slowly undergo interconversion. The enol forms give a positive reaction with ferric chloride, react rapidly with bromine, and form a peroxide with oxygen. From chemical evidence, the benzo derivatives of 3-hydroxyfuran, 28 and 29, appear to exist predominantly in the oxo form, and this is further supported by ultraviolet spectral data. Stefanye and Howard- ... 

Snyder and his co-workers assigned structures 48 and 49 to these j6-hydroxythiophene derivatives on the basis of chemical evidence and infrared and nuclear magnetic resonance spectral data. Infrared and nuclear magnetic resonance spectra further indicate that compounds of type 49 exist as dimers, probably hydrogen bonded, when R = OC2H5 or CH3, but as monomeric enols when R = H. ... 

On the basis of chemical evidence, Swiss investigators have postulated that 3,4-dihydroxythiophenes exist as diols, i.e., as 50 ... 

Hydroxypyrroles are thought to exist in oxo forms such as 51 or 52 structure 53 illustrates a third possible oxo form. Chemical evidence for tautomerism in the hydroxypyrroles has been reviewed by Fischer and Orth. " Since 2-hydroxypyrrole itself is unstable and... 

The tautomeric behavior of compounds of type 59 has been discussed by Meyer and Vaughan. An intramolecularly hydrogen-bonded 0X0 structure has been assigned to 60 on the basis of its infrared spectrum," whereas unambiguous chemical evidence, i.e., ozo-nolysis to succimide, confirmed the isolation of 61 in the oxo form. The foregoing results may be summarized as follows potential a-hydroxypyrroles exist as pyrrolones. Substituents in the 3-position and in the 5-position favor the A and the A -pyrrolone structure, respectively, as is to be expected. For 3,4,5-trisubstituted compounds, such as 61b, the A -sti ucturc appears to be preferred. An electron-... 

Less is known about the j8-hydroxypyrroles than about the isomeric a-hydroxy compounds. Originally ethyl 4-hydroxy-2-methylpyrrole-3-carboxylate was suggested, on the basis of chemical evidence, to exist as a mixture of the oxo and hydroxy forms, 64 and 65, respectively. 

Infrared and ultraviolet spectral data indicate that 1,5-diaryl-pyrrolidine-2,3-diones exist in the monooxo form 68. Chemical evidence was advanced for a tautomeric equilibrium between 69 and 70, and later spectroscopic work showed that 70 was the predominant form. " Compounds of type 71 were formulated, without experimental evidence, in the oxo-imino form, although the tendency for C=NR—>C—NHR is usually greater than that for C=0—>C—OH in analogous cases. 

Both the infrared and ultraviolet spectra of pyrrolidine-2,3,5-triones (75) have been interpreted to support their existence as hydroxy-maleimides (76), and the occurrence of a strong OH stretching band in the infrared spectrum of 4-phenylpyrrolidine-2,3,5-trione has been taken as evidence that it too exists in a hydroxy form, probably 76 (R CeHg). However, the trioxo formulation is suggested by t/j the infrared spectra of jV-substituted pyrrolidine-2,3,5-triones, although an equilibrium apparently occurs depending upon the substituents and conditions. The zwitterion formulation 77 has been advanced for 4-aminopyrrolidine-2,3,5-trione. For chemical evidence... 

An initial study of the infrared spectrum of oxindole purported to show the presence both of the hydroxy (78) and of the oxo forms (79), and, indeed, chemical evidence led to the same conclusion. On the basis of later infrared work, however, oxindole and its derivatives were considered to exist more or less completely in the oxo form, and this conclusion is supported by ultraviolet spectroscopic data, i.e., by comparison of the spectrum of the parent compound with those of its methyl derivatives. " The infrared spectrum of... 

In 1883, the hydroxy structure 82 was assigned to indoxyl on the basis of chemical evidence. More recently, however, the infrared spectra of 1-acetyl- and 1-methyl-indoxyl measured in chloroform indicated that the oxo form 83 (R = Ac, Me) greatly predominates, " ... 

---