Substituents specific substitution

Introduction of substituents on the carbocyclic ring relies primarily on electrophilic substitution and on organometallic reactions. The former reactions are not under strong regiochcmical control. The nitrogen atom can stabilize any of the C-nng o-complexes and both pyrrole and benzo ring substituents can influence the substitution pattern, so that the position of substitution tends to be dependent on the specific substitution pattern (Scheme 14.1). 

These reactions in weakly alkaline solutions are faster than the heterolytic (Dn + AN)-like hydroxy-de-diazoniation, which, for most diazonium ions, (depending on their electrophilicity), is dominant below pH 2-4. As shown by Ishino et al. (1976), an increase in rate, corresponding to the occurence of other mechanisms in addition to the heterolytic hydroxy-de-diazoniation, is observable at pH 3.7-7.0. The increase is dependent on the substituent in the specifically substituted benzenediazo-nium ion. The slope d(log )/d(pH) was found to be in the range 0.22-1.09 (see summary of the work of Ishino et al. by Zollinger, 1983, p. 624). 

The second extrathermodynamic method that we discuss here differs from Hansch analysis by the fact that it does not involve experimentally derived substitution constants (such as o, log P, MR, etc.). The method was originally developed by Free and Wilson [29] and has been simplified by Fujita and Ban [30]. The subject has been extensively reviewed by Martin [7] and by Kubinyi [8]. The method is also called the de novo approach, as it is derived from first principles rather than from empirical observations. The underlying idea of Free-Wilson analysis is that a particular substituent group at a specific substitution site on the molecule contributes a fixed amount to the biological activity (log 1/C). This can be formulated in the form of the linear relationship ... 

To further understand the mechanistic difference between aromatic substitution and the e reactions, reaction rate constants of disubstituted benzenes reacting with e were studied. Specifically, substituted benzoic acid was studied, and one substituent (-COOH) was kept constant. Table 12.6 lists the rate constants of substituted benzoic acid reacting with e. It also calculates r, which is defined as the following ... 

While the preparation of bridgehead (mono-,di-, etc.) and methylene substituted adamantanes is extremely easy, polysubstituted adamantanes in which one of the substituents is at a methylene position are much less readily prepared. In general, special techniques must be developed for each specific substitution pattern. 

Once bearing some substituents, the decrease of polarity of the sucrose derivatives makes them soluble in less-polar solvents, such as acetone or tert-butanol, in which some lipases are able to catalyze esterifications. Unlike proteases, which necessitate most often the use of an activated acyl donor (such as vinyl or trifluoroethyl esters), lipases are active with simple esters and even the parent carboxylic acids in the presence of a water scavenger. The selectivity of the lipase-catalyzed second esterification is specific for OH-6 allowing the synthesis of mixed T,6 -diesters.123,124 For some lipases, a chain-length dependence on the regiochemistry was observed.125 Selectively substituted monoesters were thus prepared and studied for their solution and thermotropic behavior.126,127 Combinations of enzyme-mediated and purely chemical esterifications led to a series of specifically substituted sucrose fatty acid diesters with variations in the chain length, the level of saturation, and the position on the sugar backbone. This allowed the impact of structural variations on thermotropic properties to be demonstrated (compare Section III.l).128... 

Different substitution patterns will be labeled with additional lowercase letters, e.g., la, lb, lc. To save space, structures available in several substitution patterns will often be drawn with no substituents. Instead, the substituents will be listed after corresponding structure symbols. For instance, la 5,10,15,20-Ph" corresponds to 5,10,15,20-tetraphenylporphyrin (la). Letter designations will be omitted when (i) there is just one substitution pattern and it is shown explicitly in the scheme, (ii) no reference to any specific substitution is made. 

The acetoacetic ester synthesis is similar to the malonic ester synthesis, but the final products are ketones specifically, substituted derivatives of acetone. In the acetoacetic ester synthesis, substituents are added to the enolate ion of ethyl acetoacetate (acetoacetic ester), followed by hydrolysis and decarboxylation to produce an alkylated derivative of acetone. 

Arene oxides 42 and 49 were obtained as minor products by an unusual thermal isomerization of the photooxide of 3-diphenylisobenzofuran. Although the thermal isomerization reaction of 3-oxaquadricyclane has been used in the synthesis of benzene oxide 1, this route to benzene oxides was initially limited to specifically substituted derivatives owing to the unavailability of the unsubstituted 7-oxanorbornadiene. Thus most of the substituted arene oxides prepared by this route contained electron-withdrawing substituents X [X = —CF3 (77), —COaMe (76, 86, 88-92, 94), and —C02Et (93)] which increased their thermal stability. 

As with the three polymeric examples, bipyridine ligands have been incorporated into polypeptides at the chain end, in the backbone, and as attached substituents. Specifically, a bipyridine has been coupled to either the amino or acid terminus of polypeptides to afford biological macroligands. For example, the 4,4 -dicarboxylic acid bipyridine was coupled to two 14-unit o-helices in order to analyze the conformation of the parallel structures.272 A triple-helical synthetic metallo-protein was formed through metal-templated self-assembly of a bipyridine unit with a 15-residue peptide substituted in the presence of metal ions.273... 

There is a difference between biphenyl- and 1,3-butadiene systems with respect to symmetry Atropisomeric biphenyl compounds, because of their dihedral symmetry, need a specific substitution pattern to be chiral. In contrast, nonplanar, helical butadienes belong to the point groups C2 or Cj and are chiral without bearing specific substituents. 

A logical next step was the investigations of 2-phenyl-naphthalenes [63]. The archetype structure 24 already showed 13-fold ERp selectivity. Substituents were incorporated at different positions and it was found that specific substitutions at C4 (e.g. 26) or C8 (e.g. 25) resulted in significantly improved ERP selectivity. Substituent... 

First attempts to predict the selectivity of enzymes are dated back to 1964 when Prelog described an empirically determined rule for the addition of hydrogen to ketones by the yeast Culvaria lunata [13]. In 1991 Kazlauskas published the hydrolysis of acetates of secondary alcohols by Pancreatic cholesterol esterase, Pseudomonas cepacia and Candida rugosa and formulated the widely applicable Kazlauskas rule according to which esters of secondary alcohols with a specific substitution pattern of large (L) and medium (M) substituents are cleaved faster than the corresponding enantiomer [14]. 

Tt has been known for 40 years that alkyllithium compounds will react with specifically substituted aromatic compounds to effect metalation —that is, replace an aromatic proton with a metal ion. More recently the orientation in a variety of such metalations has been worked out resulting in the identification of substituents that have been demonstrated to direct metalation to an aromatic proton adjacent to said substituents. This, then, is the reaction that is now called the directed metalation reaction. Since many of these substituents contain a directing nitrogen atom, it is appropriate that this process be reviewed here. 

The main difficulties associated with constructing the biaryl moiety as a single atropisomer early in the synthesis lies within the arene substitution pattern. The thermal isomerization barrier for a steganone precursor that carries only three ortho substituents is extremely sensitive to the exact identity of those substituents. Specifically, when one of the three groups (e.g., a formyl moiety) adds only a small amount to the inversion barrier and a second substituent (e.g., a methoxy group) is also relatively small, the barrier to inversion renders the biaryl stereochemically labile even at 0 For example, at least one of... 

CHCRCHCR)(HC(pz )3 ]PF6 (R = Ph, H) with the two alkynes linked head-to-tail when R = Ph. Vinylallenerhodium complexes with three kinds of coordination modes, that is, j -coordination of the terminal TT-bond of the allenyl group, if -coordination of the conjugated diene skeleton, and planar o -coordination, were synthesized by ligand substitution of RhCl(PPh3)3 with vinylallenes of specific substitution patterns (Scheme 35). Coordination preferences were explained in terms of spatial interactions between the vinylallene substituents and the phosphine ligands as well as effective delocalization of the Tt-electrons of the endo- and exocyclic double bonds. ... 

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 applicability of the two-parameter equation and the constants devised by Brown to electrophilic aromatic substitutions was tested by plotting values of the partial rate factors for a reaction against the appropriate substituent constants. It was maintained that such comparisons yielded satisfactory linear correlations for the results of many electrophilic substitutions, the slopes of the correlations giving the values of the reaction constants. If the existence of linear free energy relationships in electrophilic aromatic substitutions were not in dispute, the above procedure would suffice, and the precision of the correlation would measure the usefulness of the p+cr+ equation. However, a point at issue was whether the effect of a substituent could be represented by a constant, or whether its nature depended on the specific reaction. To investigate the effect of a particular substituent in different reactions, the values for the various reactions of the logarithms of the partial rate factors for the substituent were plotted against the p+ values of the reactions. This procedure should show more readily whether the effect of a substituent depends on the reaction, in which case deviations from a hnear relationship would occur. It was concluded that any variation in substituent effects was random, and not a function of electron demand by the electrophile. ... 

The nitration of some substituted nitrobenzenes has been studied in connection with the high o -ratios produced by [ —/ — A/] substituents. Thus nitration in sulphuric acid of 2,5-dialkyl-nitrobenzenes produces the isomer distributions shown below. As has been seen ( 9.1.3), one explanation for the occurrence of high o -ratios with [-/—A/] substituents is that the latter specifically deactivate para positions. In the... 

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