Reactions of Ring Substituents

Several different nucleophilic displacement reactions of ring substituents were utilized in the synthesis of 3-azido-oxetane-2-carboxylates (Scheme 12) <2001TL4247>. The triflate ester 66, prepared from the corresponding trans-/3-hydroxy ester and triflic anhydride, was displaced by reaction with sodium azide, and inversion of configuration, to... 

The quatemization of the nitrogen atom of the thiazole ring (the Menschutkin s reaction) by alkyl halide or methyl tosylate can be used to measure the reactivity of this atom and thus to evaluate steric and electronic effects of ring substituents. 

Fused benzene rings are treated as substituents. Thus quinoline, for example, is considered as a substituted pyridine, albeit a very special and important one, and treated alongside other substituted pyridines in the discussion of its structure, reactivity and synthesis. Reactions of quinoline at positions 1-4 are considered as reactions at ring atoms, whilst reactions at positions 5-8 are regarded as reactions of the substituent . 

Analogous results were obtained for enol ether bromination. The reaction of ring-substituted a-methoxy-styrenes (ref. 12) and ethoxyvinylethers (ref. 10), for example, leads to solvent-incorporated products in which only methanol attacks the carbon atom bearing the ether substituent. A nice application of these high regio-and chemoselectivities is found in the synthesis of optically active 2-alkylalkanoic acids (ref. 13). The key step of this asymmetric synthesis is the regioselective and chemoselective bromination of the enol ether 4 in which the chiral inductor is tartaric acid, one of the alcohol functions of which acts as an internal nucleophile (eqn. 2). 

The very small p- and m-values observed for the fast bromination of a-methoxystyrenes deserve comment since they are the smallest found for this electrophilic addition. The rates, almost but not quite diffusion-controlled, are amongst the highest. The sensitivity to polar effects of ring substituents is very attenuated but still significant that to resonance is nil. These unusually low p-values for a reaction leading to a benzylic carbocation are accompanied by a very small sensitivity to the solvent. All these data support a very early transition state for this olefin series. Accordingly, for the still more reactive acetophenone enols, the bromination of which is diffusion-controlled, the usual sensitivity to substituents is annulled. 

Some key reactions relevant to this section were not covered in CHEC-II(1996) <1996CHEC-II(4)179>, and hence some references to important work prior to the appearance of CHEC-IK1996) are included. Nonetheless, CHEC-11(1996) does contain many pertinent reactions of ring carbon substituents, such as important information on Curtius rearrangements and a-anion formation and reactivity. 

Only a few reactions of the substituents attached to ring carbon atoms of bicyclic systems 1-34 have been reported. Methylation of compound 100 occurs at sulfur to give 101 (Equation 6) <2005BMC1847>. Horner-Emmons reaction of phosphonate 102 with benzaldehyde leads to triazole 103 as a single /. -stereoisomer (Equation 7) <2004TL1877>. 

The effect of ring substituents on the rate constants, deuterium kinetic isotope effects and Arrhenius parameters for ene-additions of acetone to 1,1-diphenylsilane have been explained in terms of a mechanism involving fast, reversible formation of a zwitterionic silene-ketone complex, followed by a rate-limiting proton transfer between the a-carbonyl and silenic carbon. A study of the thermal and Lewis acid-catalysed intramolecular ene reactions of allenylsilanes with a variety of... 

The most important reactions of alkyl substituents a and y to the ring heteroatom are those which proceed via base-catalyzed deprotonation. Treatment of 2- and 4-alkyl heterocycles with strong bases such as sodamide and liquid ammonia, alkyllithiums, LDA, etc., results in an essentially quantitative deprotonation and formation of the corresponding carbanions. These then react normally with a wide range of electrophiles such as alkyl halides and tosylates, acyl halides, carbon dioxide, aldehydes, ketones, formal-dehyde/dimethylamine, etc., to give the expected condensation products. Typical examples of these transformations are shown in Scheme 17. Deprotonation of alkyl groups by the use of either aqueous or alcoholic bases can also be readily demonstrated by NMR spectroscopy, and while the amount of deprotonation under these conditions is normally very small, under the appropriate conditions condensations with electrophiles proceed normally (Scheme 18). 

Some reactions of the substituents attached to ring heteroatoms have been partly described in CHEC-II(1996) <1996CHEC-II(7)1>. 

Figure 2.2. The change with changing aromatic ring substituent X in the azide (az) ion selectivities (feaz/ s)obsd ( ) determined by analysis of the products of the reactions of ring-substituted 1-phenylethyl derivatives (X-l-Y) and ring-substituted cumyl derivatives (X-2-Y) in 50/50 (v/v) water/trifluoroethanol at 25 The selectivities are plotted...

Figure 2.5. Nucleophile selectivities determined from product analysis for the reactions of ring-suhstituted 1-phenylethyl derivatives (X-l-Y) with azide ion, acetate ion and methanol in 50 50 (v/v) water/trifluoroethanol. The selectivities are plotted against the appropriate Hammett substituent constant or a. Leaving group Y ( ) ring-suhstituted benzoates ( ) chloride (T) dimethyl sulfide (A) tosylate.

In all cases the boron goes to the side of the double bond that has more hydrogens, whether the substituents are aryl or alkyl.35B Thus the reaction of 43 with BH3 gives 98% 44 and only 2% of the other product. This actually follows Markovnikov s rule, since boron is more positive than hydrogen. However, the regioselectivity is caused mostly by steric factors, though electronic factors also play a part. Studies of the effect of ring substituents on rates and on the direction of attack in hydroboration of substituted styrenes showed that the attack by boron has electrophilic character.359 When both sides of the double bond are... 

In aliphatic compounds, reactions of functional groups are often modified very significantly by an adjacent carbonyl group. As would be expected from the discussion in the preceding section, the reactions of certain substituents a and y to pyridine-like nitrogen atoms in azole rings are similarly influenced. Such effects on substituents can be classified into six groups. 

With this section, the classification in the Handbook of Heterocyclic Chemistry has been followed thus a general survey of the effect of rings on the reactions of substituents is followed by a survey of the effect of rings on reactions of individual substituents in the order fused benzene rings, C-linked, AMinked, <9-linked, S-linked substituents, halogens, and metals. Substituents attached to cyclic nitrogen and sulfur are dealt with as described below. 

SAMPLE SOLUTION (a) The ring that bears the hydroxyl group is much more reactive than the other ring. In electrophilic aromatic substitution reactions of rings that bear several substituents, it is the most activating substituent that controls the orientation. Bromination occurs para to the hydroxyl group. 

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