Controlling Positional Isomers

As described above, high-resolution reaction time control enables switching product selectivity at will. A product derived from a reactive species that has yet to be isomerized can be obtained by setting a shorter reaction time, or a product derived from an isomerized reactive species can be obtained by setting a longer reaction time. 

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Because the product composition is kinetically controlled, the isomer ratio will be governed by the relative magnitudes of AG, AGI, and AG, the energies of activation for the ortho, meta, and para transition states, respectively. In Fig. 4.7 a qualitative comparison of these AG values is made. At the transition state, a positive charge is present on the benzene ring, primarily at positions 2, 4, and 6 in relation to the entering bromine. 

Argentation thin-layer chromatography is an extemely useful procedure for the separation of methyl esters of fatty acids. Saturated fatty acids have the highest Rf values, which decrease with the increasing degree of unsaturation, and for a particular acid, the trans isomer usually travels ahead of its corresponding cis isomer. The solvents most commonly used contain hexane and diethyl ether (9 1) although a mixture of 4 6 is used to separate compounds with more than two double bonds. In order to separate positional isomers of the same acid, conditions must be carefully controlled and multiple development in toluene at low temperatures is often necessary. 

Additional modes of HPTC include normal phase, where the stationary phase is relatively polar and the mobile phase is relatively nonpolar. Silica, diol, cyano, or amino bonded phases are typically used as the stationary phase and hexane (weak solvent) in combination with ethyl acetate, propanol, or butanol (strong solvent) as the mobile phase. The retention and separation of solutes are achieved through adsorp-tion/desorption. Normal phase systems usually show better selectivity for positional isomers and can provide orthogonal selectivity compared with classical RPLC. Hydrophilic interaction chromatography (HILIC), first reported by Alpert in 1990, is potentially another viable approach for developing separations that are orthogonal to RPLC. In the HILIC mode, an aqueous-organic mobile phase is used with a polar stationary phase to provide normal phase retention behavior. Typical stationary phases include silica, diol, or amino phases. Diluted acid or a buffer usually is needed in the mobile phase to control the pH and ensure the reproducibility of retention times. The use of HILIC is currently limited to the separation of very polar small molecules. Examples of applications... 

Coupling of 834 with 783 gave 835, which cyclized to 836 (92MI8). However, treatment of the sodium salt of 839 with 783 afforded a mixture of two major positional isomers of nucleosides. The reaction is thermodynamically controlled. At room temperature the N-1 isomer predominates, whereas formation of the N-7 isomer increases with an increase in temperature. Debromination of the mixture gave 840 and 841, which could be separated. 

C), has proven to be too reactive and nonselective towards alkenes. In the presence of 2 % ethanol, bromine monofluoride adds to C = C bonds at controllable rates but bromo ether byproducts arc formed that make the isolation of the desired bromofluoroalkanes difficult. The addition of bromine monofluoride is less regioselective compared to the addition of iodine monofluoride positional isomers are always present in the reaction mixture together with the major Markovnikov-typc addition products. 

When w.//-perfluoroalk-l-enes longer than butene [CHF2(CF2)nCF = CF2, n = 2-7] are isomerized under conditions of thermodynamic control, however, mixtures of all possible positional isomers are obtained. Isomerization of these aik-1 -enes with antimony(V) fluoride under conditions of kinetic control yields the corresponding alk-2-enes as an EjZ mixture.20... 

In competitive substrate binding experiments, the polymers showed selectivity for the templates with which they were made. On the other hand, non-templated control polymers showed statistical preference for both substrates. Some results on the substrate selectivities of these polymers are presented in Table 6.1. It is particularly notable from this study that these imprinted polymers could distinguish positional isomers (4 and 5), which differ in their imidazole spacing by only 4 A. 

Because of our earlier observations that octopamine might be a neurotransmitter in insects but not vertebrates, several years ago we carried out an experiment to determine whether large doses of exogenous octopamine might exert detrimental behavioral effects in insects, analogous to what might happen if a vertebrate received an overdose of adrenalin or amphetamine. As a control, we decided to compare the activity of octopamine (chemically para-octopamine) with a positional isomer, meta-octopamine, which we found had little activity on insect adenylate cyclase (17). 

Another computational study of aromaticity was based on -center delocalization indexes ( -DIs) and led to the conclusion that the order of stability within a series of position isomers (here 1,2,3-, 1,2,4-, and 1,3,5-triazine) is not controlled by aromaticity. The least stable isomer was found to be the most aromatic one (relative energies in kcal mol , 6-DIs in parentheses) within that series 1,2,3-triazine 1 (44.0, 2.75), 1,2,4-triazine (27.3, 2.47), and 1,3,5-triazine (0.0, 2.32) for comparison benzene 2.67 <2006T12204> compare Section 9.01.2.8. 

Liquid chromatography Normal-phase systems have the advantage of being directly compatible with extracts in hexane. Silica, alumina, and lime (calcium hydroxide) are all particularly suited to the resolution of carotenoid geometrical isomers cis-trans) and diastereoisomers, but not positional isomers oc/fi-carotene). However, silica may cause on-column artifacts, reproducible retention on alumina is strongly dependent on a rigorous control of the water content of the eluent, and lime columns are not commercially available. 

A monoester of sucrose prepared from a pure fatty acid methyl ester by transesterification is a mixture of positional isomers (15-20). Each isomer could behave differently in bread. Data in Figure 4 show a dramatic example of how positional isomers function differently in breadmaking (2) ). L-Ascorbyl 6-palmi-tate is an excellent dough strengthener, which showed a +92 cc volume response above a no-shortening control loaf (905 cc). On the other hand, L ascorbyl 2-palmi-tate decreased loaf volume 165 cc below the control. 

Metallated methylenecyclobutane has been used as an isoprene equivalent in terpene synthesis. Methylenecyclobutene has been metallated with butyl-lithium and tetramethylethylenediamine. Reaction of the ambident anion (384) with electrophiles gives a mixture of positional isomers. The ratio of the isomers can be controlled by variation of solvent and temperature in this reaction and the cyclobutene ring in the products can then be opened thermally to dienes. This method has been applied to a synthesis of a component of the Ips confusus pheromone. Reaction of (384) with iso-valeraldehyde gave 30 % of the cyclobutene (385) which was isomerized to (386) by heating at 150°C. 

When position isomers are formed, it almost always is necessary to effect a separation because the isomers differ in properties and lead to different dyes. One of the most difficult problems in the manufacture of dye intermediates is the efficient separation of isomers. A further problem is to control the relative quantities in which isomers are formed or to find uses for all of them in the event that control is impractical. 

The major drawbacks concerning the use of dienes in cycloisomerization reactions usually rely on the poor control of the regiochemical outcome, based on the lack of significant reactivity difference between the reacting alkenes. What is more, olefinic positional isomers are commonly obtained due to the facile transposition of alkenes via the reversible hydrometallation/p-hydride elimination, which is usually feasible during the standard cycloisomerization conditions (Scheme 7.34). To address these issues, considerable efforts have been directed... 

N-Unsubstituted 1,2,3-triazoles are methylated mainly in the 1-position with methyl iodide and silver or thallium salts, but mainly in the 2-position by diazomethane. There is also some steric control. For example, 4-phenyl-l,2,3-triazole with dimethyl sulfate gives the 2-methyl-4-phenyl (38%) and l-methyl-4-phenyl isomers (62%), but none of the more hindered 1-methyl-5-phenyltriazole (74AHC(16)33). JV-Unsubstituted 1,2,4-triazoles are generally alkylated at N-1. 

The same arguments can be applied to other energetically facile interconversions of two potential reactants. For example, many organic molecules undergo rapid proton shifts (tautomerism), and the chemical reactivity of the two isomers may be quite different It is not valid, however, to deduce the ratio of two tautomers on the basis of subsequent reactions that have activation energies greater than that of the tautomerism. Just as in the case of conformational isomerism, the ratio of products formed in subsequent reactions will not be controlled by the position of the facile equilibrium. 

The relative stability of the intermediates determines the position of substitution under kinetically controlled conditions. For naphthalene, the preferred site for electrophilic attack is the 1-position. Two factors can result in substitution at the 2-position. If the electrophile is very bulky, the hydrogen on the adjacent ring may cause a steric preference for attack at C-2. Under conditions of reversible substitution, where relative thermodynamic stability is the controlling factor, 2-substitution is frequently preferred. An example of this behavior is in sulfonation, where low-temperature reaction gives the 1-isomer but at elevated temperatures the 2-isomer is formed. ... 

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