Solvent effects on regioselectivity

A common problem in the manufacture of fine chemicals is that a substrate may have more than one reactive site. A well known, but intractable, problem is the nitration of monosubstituted benzenes, which always leads to a mixture of isomers. Reactions which involve nucleophilic substitution are more amenable to control of regioselectivity by choice of solvent. An excellent review on the reactivity of ambident anions is available, in which this subject is treated [17]. An instructive example is the alkylation of phenol with allyl chloride [18] (equation 12.10). Table 12.13 shows how the properties of O- and C-alkylation are affected by solvent. 

These results are interpreted in terms of selective solvation of the more electronegative site, i.e. oxygen, by the more protic solvents, leading to carbon alkylation. In solvents which are less good as proton donors the 

Solvent allyl chloride allyl bromide % 0-allylation % C allylation 

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Many mechanisms had been proposed in the past to rationalize this selectivity (tri-oxanes, perepoxide, exciplex, dipolar or biradical intermediates) however, it is now generally accepted that the reaction proceeds through an intermediate exciplex which has the structural requirements of a perepoxide. This assumption is supported by (a) the lack of stereoselectivity in the reactions with chiral oxazolines and tiglic acid esters (b) the comparison of the diastereoselectivity of dialkyl substituted acrylic esters with structurally similar non-functionalized aUtenes (c) the intermolecular isotope effects in the photooxygenation of methyl tiglate and (d) the solvent effects on regioselectivity. ... 

Table 5. Solvent effects on regioselectivity in the additions of pyrollidine and n-propylamine to 2-furyl- and phenyl-propiolic acid derivatives, X—R—C=CCOY (equation 53) >...

The solvent has no influence on the stereoselectivity of bromine addition to alkenes (Rolston and Yates, 1969b), but it could have some effect on the regioselectivity, since this latter depends not only on polar but also on steric effects. Obviously, it modified the chemoselectivity. For example, in acetic acid Rolston and Yates find that 2-butenes give 98% dibromides and 2% solvent-incorporated products whereas, in methanol with 0.2 m NaBr, dibromide is only about 40% and methoxybromide 60%. There are no extensive data, however, on the solvent effects on the regio- and chemoselectivity which would allow reliable predictions. 

In summary, the interactions responsible for the typical solvent effects on Diels-Alder reactions are comparable to those of Lewis acids. The rate acceleration, the increase of regioselectivity and the higher endo/exo selectivity on changing the solvent may be explained by the FMO theory. 

A study of the intramolecular alkoxymercuration of ( )-5-arylpent-4-en-l-ols (70) has indicated that the regioselectivity is closely related to the Hammett constants of the para-substituents on the benzene ring. Large solvent effects on the regioselectivity were also observed (Scheme 17 and Tables 2 and 3). By contrast, the related oxymercuration of -methylstyrene is 100% a-sclcctivc. This comparison shows that the regioselectivity of the intermolecular reaction is controlled by electronic factors, whereas the cyclization is governed by a delicate balance of steric and electronic effects.65... 

It should be noted that the stereoselectivity is also completely different from that associated with triplet 1,4-biradicals. Thus, a highly exo-selective formation ofbicyclic oxetanes was observed during PET-promoted PB reactions, whereas a highly endo-selective formation ofbicyclic oxetanes was reported for PB reactions that proceeded via triplet 1,4-biradicals (see Scheme 7.25). The competitive reaction pathway for electron-rich alkenes explained a notable solvent effect on the regioselectivity and stereoselectivity of the PB reaction of dihydrofuran (Scheme 7.15). Thus, an endo-selective formation of 3-alkoxyoxetane was observed when using benzene, whereas the exo-isomer of 2-alkoxyoxetane was detected as a product of the PB reaction in acetonitrile (Scheme 7.15). 

As measured by the criteria of stereospecificity, regioselectivity, kinetic isotope effects, and solvent effects [117-120, 541-543], 1,3-dipolar cycloaddition reactions represent orbital symmetry-allowed [n + n s] cycloadditions, which usually follow concerted pathways Diels-Alder reactions and 1,3-dipolar cycloadditions resemble each other, as demonstrated by the small solvent effects on their bimolecular rate constants. In going from nonpolar to polar solvents, the rate constants of 1,3-dipolar cycloadditions change only by a factor of 2... 10 [120, 131-134]. 

The solvent effect on the regioselectivity of the AuCls-catalyzed cycloisomerization of a bromoallenyl ketone was evaluated by density functional theory calculations. Upon the generation of the gold carbenoid intermediate from cyclization of the aUene precursor, the tetrahydrofiiran solvent can act as a proton shuttle to assist the 1,2-H migration to afford the 2-bromofuran product (14S2149). 

Further studies have come from the DeBoef group on oxidant-controlled regioselectivity, in which both benzofuran and indole arylations were examined in different solvent parameters. They surmised that solvent had little overall effect on regioselectivity compared to oxidant choice, and both DeBoef and Fagnou reasoned that site selectivity is most likely due to the formation of polymetallic clusters during catalysis. " ... 

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