Side-chain reactions

Various Side-chain Reactions.—2-(2-Thienyl)ethyl isocyanate has been prepared from the corresponding primary amine, carbonyi suiphide, and. S-ethyl chloro-thioformate. Cyclization of 2-(2-thienyl)ethyl isothiocyanate with methyl fluorosulphonate or triethyloxonium tetrafluoroborate gave (178a) and (178b), respectively. The 3-thienyl isomer reacted in the same way. Monoesters of aliphatic dicarboxylic acids and 2-(2-thienyl)ethanol have been prepared in con- 

Various Side-chain Reactions.— The condensation product between 2-methyl- and 2-ethyl-thiophen-4-aldehyde and nitroethane (182) was transformed into (183) by treatment with iron and hydrochloric acid. The carbanion from methyl 2-thenylsulphoxide reacts with ethyl benzoate to give (184), which by aluminium amalgam was reduced to 2-thenyl phenyl 

Arcoria, S. Fisichella, G. Scarlata, and M. Torre, Chimica e Industria, 1973, 55, 789. 

10-dibromoanthracene is an efficient catalyst for the oxidation of 2-methylthiophen. From 2,5-dimethylthiophen the dicarboxylic acid is obtained in 91% yield. Both 2-methyl-3-nitrothiophen and 3-methyl-2-nitrothiophen have been condensed to styryl derivatives with benzal-dehydes in the presence of catalytic amounts of pyrrolidine. The copper-catalysed reaction of thiophen-2-sulphonyl chloride with styrene gives (192), which through elimination of hydrogen chloride with triethylamine and reaction with dimethylsulphonium methylide was transformed into (193). A method for the synthesis of esters of thiophen-2,5- 

Cisoid retinoids have been isomerized to give the corresponding trans compounds by catalysis with iodine (Cainelli etal, 1973 Reif and Grassner, 1973). Methyl (13Z)-retinoate (176) has been converted to (all- )-retinoic acid (3) by being treated at room temperature with potassium amide in toluene and hydrolysis of the product obtained (Matsui, 1962). Homogeneous catalysis of a mixture of (9Z)-retinyl acetate (366) and (all- )-retinyl acetate (9) in the presence of palladium(II) chloride/acetonitrile adducts gave, by isomerization, a mixture more concentrated in (9), and pure (all- )-retinyl acetate (9) was then isolated in crystalline form from the latter mixture (Stoller and Wagner, 1975 Fischli et al., 1976). 

The thermal decomposition of the ester (47) gave an equilibrium mixture of the compounds (48), (49), and (50). 

It is possible that this mixture is formed by trans-cis isomerization of (47) to the thermally unstable 8Z ester that undergoes subsequent electrocyclic reactions (Loeliger and Mayer, 1980). 

Retinoids are readily protonated. Investigations of the mechanism of protonation of anhydroretinol (58) with anhydrous hydrogen chloride showed that very complex ionic mixtures were formed (Bulgrin and Lockhart, 1974). The retinyl carbonium ion ( = 585 nm) has been characterized in the protonation of retinol (1) (Bobrowski and Das, 1982). The color change after protonation with about 80% sulfuric acid was utilized for the quantitative determination of retinoic acid (3). The acids (51) and (52), after quenching of the red carbonium ions, were determined to be rearrangement products (Tsukida et aL, 1978a, 1980, 1981 Ito eta/., 1980). 

The Carr-Price reaction for the colorimetric determination of retinoids, which has long been in use, is based on colored cations formed via antimony (III) chloride (Hubbard et aL, 1971 Blatz and Estrada, 1972 Bridges and Alvarez, 1982). In the same way, the protonation of retinoids with trifluoroacetic acid has been used for colorimetric analysis (Dugan et aL, 1964). 

Taylor reported pyrolysis rates for l-(2 - and -3 -thiophenyl)ethyl acetates at temperatures between 318 and 379°C [68JCS(B)1397]. Comparison with data for 1-phenylethyl acetate gave log k/k0 values at 600 k of 0.524 and 0.251, respectively, and hence o-J = -0.795 and o-3 = -0.38 

Solvolysis of the same compounds in 30% aqueous ethanol at 25°C by Hill et al. (69JA7381) gave klk0 values of 5.4 X 104 and 480, respectively, hence aj = -0.83 and at = -0.47 (p = -5.7). 5-Methyl and 5-bromo substituents altered the reactivity of the 2-position by factors of 74 and 

In this reaction, partial rate factors (relative to reaction at the 2-position) were determined (Table 6.11) (72JOC2615), and if the points for the C02Et substituents are excluded (5-C02Et is particularly deviant), a very good correlation with cr+ is obtained (p = -6.7), and again the effects of 

Rate Factors (Relative to the 2-Position of the Heterocycle) for Solvolysis of Substituted 1-(2-Aryl)ethyl p-Nitrobenzoates at 25°C  

The reactivity of the 2-position of thiophenes has been determined in three other reactions proceeding via formation of a carbocation at the side-chain a-position. In the solvolysis of 1-arylethyl chlorides, / = 16,070, hence cr+2 = -0.78 (p = -5.4) [75JCS(P2)551]. In the isomerization of c/.s-l-aryl-2-phenylethenes in aqueous sulfuric acid, f2 = 350, hence cr+2 = -0.77 (p = -3.3) (68JA4633 70JOC1718). For the rearrangement of l-arylbut-2-en-l-ols,/2 = 35, giving cr+2 = -0.595 (p calculated as -2.6 at 25°C from the relative rate of the p-methoxyphenyl compound) (52JCS1528). 

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There were two schools of thought concerning attempts to extend Hammett s treatment of substituent effects to electrophilic substitutions. It was felt by some that the effects of substituents in electrophilic aromatic substitutions were particularly susceptible to the specific demands of the reagent, and that the variability of the polarizibility effects, or direct resonance interactions, would render impossible any attempted correlation using a two-parameter equation. - o This view was not universally accepted, for Pearson, Baxter and Martin suggested that, by choosing a different model reaction, in which the direct resonance effects of substituents participated, an equation, formally similar to Hammett s equation, might be devised to correlate the rates of electrophilic aromatic and electrophilic side chain reactions. We shall now consider attempts which have been made to do this. 

The suitability of the model reaction chosen by Brown has been criticised. There are many side-chain reactions in which, during reaction, electron deficiencies arise at the site of reaction. The values of the substituent constants obtainable from these reactions would not agree with the values chosen for cr+. At worst, if the solvolysis of substituted benzyl chlorides in 50% aq. acetone had been chosen as the model reaction, crJ-Me would have been —0-82 instead of the adopted value of —0-28. It is difficult to see how the choice of reaction was defended, save by pointing out that the variation in the values of the substituent constants, derivable from different reactions, were not systematically related to the values of the reaction constants such a relationship would have been expected if the importance of the stabilization of the transition-state by direct resonance increased with increasing values of the reaction constant. 

Section 11 10 Chemical reactions of arenes can take place on the ring itself or on a side chain Reactions that take place on the side chain are strongly influ enced by the stability of benzylic radicals and benzylic carbocations... 

Acyl Side-Chain Reactions. Many reactions occur in the R group of the fatty acid residue (see Carboxylic acids Fats and fatty oils). 

Rate data are also available for the solvolysis of l-(2-heteroaryl)ethyl acetates in aqueous ethanol. Side-chain reactions such as this, in which a delocalizable positive charge is developed in the transition state, are frequently regarded as analogous to electrophilic aromatic substitution reactions. In solvolysis the relative order of reactivity is tellurienyl> furyl > selenienyl > thienyl whereas in electrophilic substitutions the reactivity sequence is furan > tellurophene > selenophene > thiophene. This discrepancy has been explained in terms of different charge distributions in the transition states of these two classes of reaction (77AHC(21)119>. 

The classic example, and still the most useful one, of a LFER is the Hammett equation, which correlates rates and equilibria of many side-chain reactions of meta- and para-substituted aromatic compounds. The standard reaction is the aqueous ionization equilibrium at 25°C of meta- and para-substituted benzoic acids. 

Bromination of polymethylbenzenes by Br in CH3NO2 Electrophilic side-chain reactions 25 -8.10... 

Probably the most important development of the past decade was the introduction by Brown and co-workers of a set of substituent constants,ct+, derived from the solvolysis of cumyl chlorides and presumably applicable to reaction series in which a delocalization of a positive charge from the reaction site into the aromatic nucleus is important in the transition state or, in other words, where the importance of resonance structures placing a positive charge on the substituent - -M effect) changes substantially between the initial and transition (or final) states. These ct+-values have found wide application, not only in the particular side-chain reactions for which they were designed, but equally in electrophilic nuclear substitution reactions. Although such a scale was first proposed by Pearson et al. under the label of and by Deno et Brown s systematic work made the scale definitive. 

Although the application of the Hammett equation to side-chain reactions of disubstituted benzene derivatives (1) is relatively straightforward, the introduction of a heteroatom somewhere in the aromatic... 

Side chain reaction in derivatives of compound 2 has largely been concerned with the production of compounds with pharmaceutical activity by reaction between chloroalkyl side chains in position 2 and suitable amines. A selection of such compounds are 224 (82JAP(K)206684), and 225 (81FRP2450259) both are antihypertensive. Use of a dichloromethyl side chain provides an unsaturated amine, as in compound 226 (81FRP2450259). 

Antispasmodic activity, interestingly, is maintained even in the face of the deletion of the ethanolamine ester side chain. Reaction of anisaldehyde with potassium cyanide and dibutylamine hydrochloride affords the corresponding a-aminonitrile (72) (a functionality analogous to a cyanohydrin). Treatment with sulfuric acid hydrolyzes the nitrile to the amide to yield ambucet-amide (73). ... 

The Hammett equation is the best-known example of a linear free-energy relationship (LFER), that is, an equation which implies a linear relationship between free energies of reaction or activation for two related processes48. It describes the influence of polar meta-or para-substituents on reactivity for side-chain reactions of benzene derivatives. 

The symbol k or K is the rate or equilibrium constant, respectively, for a side-chain reaction of a meta- or para-substituted benzene derivative, and k° or K° denotes the statistical quantity (intercept term) approximating to k or K for the parent or unsubstituted compound. The substituent constant a measures the polar (electronic) effect of replacing H by a given substituent (in the meta- or para-position) and is, in principle, independent of the nature of the reaction. The reaction constant p depends on the nature of... 

Data for other p-substituted benzene side-chain reactions are fitted by eq. (1) using the oj and Or values of Table I with widely varying precision measures. However, precision of fit comparable to that achieved for the eight basis set reactions of Table II is obtained (only) with recognizable analogs of the para BA type. Other reaction types are fitted generally with values of / SD/RMS greater by factors of two or more than the i>% level achieved by the para BA type (cf. subsequent Tables VII, IX, XII, XIV). 

In spite of ionization at a greater distance for the ortho and para positions of the side-chain reaction centers, pr is greater at these positions for ArNHs than for pyr H. Only at the meta position does pr reflect ionization at a greater distance in ArNHa than pyr H. This behavior provides evidence for the much smaller importance of direct quinoidal interaction within the ring than across it i.e.. 

It appeared to the author some years ago that, irrespective of the mechanism of the toxic action of DDT, there might be a correlation of structure and toxicity in analogous compounds. Hammett (13) has shown that the rate and equilibrium constants of over 50 side-chain reactions of meta and para substituted aromatic compounds may be correlated with the so-called substituent constant a, according to the equation log k — log k0 = pa, where k and k0 are rate (or equilibrium) constants for substituted and unsubstituted compounds, respectively, p is the reaction constant giving the slope of the linear relationship, and a is the substituent constant, which is determined by the nature and... 

Quite early on (p. 361) in this discussion of linear free energy relationships consideration was restricted to the side-chain reactions of m- and p-substituted benzene derivatives. The reactions of o-substituted benzene derivatives, and indeed of aliphatic compounds, were excluded because of the operation of steric and other effects, which led to non-linear, or even to apparently random, plots. 

The Hammett equation is the best-known and most widely studied of the various linear free energy relations for correlating reaction rate and equilibrium constant data. It was first proposed to correlate the rate constants and equilibrium constants for the side chain reactions of para and meta substituted benzene derivatives. Hammett (37-39) noted that for a large number of reactions of these compounds plots of log k (or log K) for one reaction versus log k (or log K) for a second reaction of the corresponding member of a series of such derivatives was reasonably linear. Figure 7.5 is a plot of this type involving the ionization constants for phenylacetic acid derivatives and for benzoic acid derivatives. The point labeled p-Cl has for its ordinate log Ka for p-chlorophenylacetic acid and for its abscissa log Ka for p-chloroben-zoic acid. The points approximate a straight line, which can be expressed as... 

Bakhshi, A. K., and J. Ladik. 1986. Ab Initio Study of the Effect of Side-Chain Reactions on the Electronic Structure of Proteins. Chem. Phys. Letters 129, 269-274. 

This review of furan chemistry is meant to continue the earlier survey by Bosshard and Eugster1 and concentrates upon the period 1968 to the end of 1979. Like the earlier review, this one is limited to the chemistry of the monocyclic furan nucleus and does not deal, except incidentally, with fused rings such as benzofuran or its quinones. Nor does it deal in detail with dihydro- or tetrahydrofurans, nor with compounds like furylpyridine that contain some other heterocyclic nucleus as well. Some butenolides and tetronic acids are admitted to consideration since they are the carbonyl equivalents of hydroxyfurans regarded as enols, but side-chain reactions are wholly excluded unless the furan nucleus clearly affects them in some important way. 

The effect of a substituent on the aromatic substitution reaction is similar to its effect on electrophilic side chain reactions, but not precisely parallel. Thus the Hammett relationship using the usual sigma or substituent constants gives considerable scatter when applied to aromatic substitution. The scatter is probably due to an increased importance of resonance effects in the nuclear substitution reaction as compared with the side chain reactions. 

Simple side-chain reactions of 1,2-dithiin diols have been conducted. Besides the formation of esters, ethers (R = Me, Et, 7-Pr, cyclopropyl, Ph, pyridyl, cyclopentyl), and thioethers (R = H, TBDMS R = 4 -(4-hydroxyphenyl)-l//-tetrazole-5-thiol), selective oxidation of the primary alcohol groups in the presence of the 1,2-dithiin heterocycle could be readily achieved (Scheme 36) <1995JME2628, 1994SL201>. Additionally, amides, ureas, and carbamates of the dithiin diol were synthesized <1995JME2628>. 

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